Compounds useful as anti-inflammatory agents

ABSTRACT

Disclosed are novel aromatic compounds which are useful for treating diseases or pathological conditions involving inflammation such as chronic inflammatory diseases. Also disclosed are pharmaceutical compositions containing and processes of making such compounds.

APPLICATION DATA

This application is a divisional application of U.S. Ser. No. 09/505,582filed Feb. 16, 2000, now U.S. Pat. No. 6,358,945, which claims benefitof U.S. provisional application No. 60/124,148 filed Mar. 12, 1999 andU.S. provisional application No. 60/165,867 filed Nov. 16, 1999.

TECHNICAL FIELD OF THE INVENTION

This invention relates to novel compounds which inhibit production ofcytokines involved in inflammatory processes and are thus useful fortreating diseases and pathological conditions involving inflammationsuch as chronic inflammatory disease. This invention also relates toprocesses for preparing these compounds and to pharmaceuticalcompositions comprising these compounds.

BACKGROUND OF THE INVENTION

Tumor necrosis factor (TNF) and interleukin-1 (IL-1) are importantbiological entities collectively referred to as proinflammatorycytokines. These, along with several other related molecules, mediatethe inflammatory response associated with the immunological recognitionof infectious agents. The inflammatory response plays an important rolein limiting and controlling pathogenic infections.

Elevated levels of proinflammatory cytokines are also associated with anumber of diseases of autoimmunity such as toxic shock syndrome,rheumatoid arthritis, osteoarthritis, diabetes and inflammatory boweldisease (Dinarello, C. A., et al, 1984, Rev. Infect. Disease 6:51). Inthese diseases, chronic elevation of inflammation exacerbates or causesmuch of the pathophysiology observed. For example, rheumatoid synovialtissue becomes invaded with inflammatory cells that result indestruction to cartilage and bone (Koch, A. E., et al., 1995, J. Invest.Med. 43: 28-38). An important and accepted therapeutic approach forpotential drug intervention in these diseases is the reduction ofproinflammatory cytokines such as TNF (also referred to in its secretedcell-free form as TNFα) and IL-1β. A number of anti-cytokine therapiesare currently in clinical trials. Efficacy has been demonstrated with amonoclonal antibody directed against TNFα in a number of autoimmunediseases (Heath, P., “CDP571: An Engineered Human IgG4 Anti-TNFαAntibody” IBC Meeting on Cytokine Antagonists, Philadelphia, Pa., Apr.24-5, 1997). These include the treatment of rheumatoid arthritis,Crohn's disease and ulcerative colitis (Rankin, E. C. C., et al., 1997,British J. Rheum. 35: 334-342 and Stack, W. A., et al., 1997, Lancet349: 521-524). The monoclonal antibody is thought to function by bindingto both soluble TNFα and to membrane bound TNF.

A soluble TNFα receptor has been engineered that interacts with TNFα.The approach is similar to that described above for the monoclonalantibodies directed against TNFα; both agents bind to soluble TNFα, thusreducing its concentration. One version of this construct, called Enbrel(Immunex, Seattle, Wash.) recently demonstrated efficacy in a Phase IIIclinical trial for the treatment of rheumatoid arthritis (Brower et al.,1997, Nature Biotechnology 15: 1240). Another version of the TNFαreceptor, Ro 45-2081 (Hoffman-LaRoche Inc., Nutley, N.J.) hasdemonstrated efficacy in various animal models of allergic lunginflammation and acute lung injury. Ro 45-2081 is a recombinant chimericmolecule constructed from the soluble 55 kDa human TNF receptor fused tothe hinge region of the heavy chain IgG1 gene and expressed ineukaryotic cells (Renzetti, et al., 1997, Inflamm. Res. 46: S143).

IL-1 has been implicated as an immunological effector molecule in alarge number of disease processes. IL-1 receptor antagonist (IL-1ra) hadbeen examined in human clinical trials. Efficacy has been demonstratedfor the treatment of rheumatoid arthritis (Antril, Amgen). In a phaseIII human clinical trial IL-1ra reduced the mortality rate in patientswith septic shock syndrome (Dinarello, 1995, Nutrution 11, 492).Osteoarthritis is a slow progressive disease characterized bydestruction of the articular cartilage. IL-1 is detected in synovialfluid and in the cartilage matrix of osteoarthritic joints. Antagonistsof IL-1 have been shown to diminish the degradation of cartilage matrixcomponents in a variety of experimental models of arthritis (Chevalier,1997, Biomed Pharmacother. 51, 58). Nitric oxide (NO) is a mediator ofcardiovascular homeostasis, neurotransmission and immune function;recently it has been shown to have important effects in the modulationof bone remodeling. Cytokines such as IL-1 and TNF are potentstimulators of NO production. NO is an important regulatory molecule inbone with effects on cells of the osteoblast and osteoclast lineage(Evans, et al., 1996, J Bone Miner Res. 11, 300). The promotion ofbeta-cell destruction leading to insulin dependent diabetes mellitusshows dependence on IL-1. Some of this damage may be mediated throughother effectors such as prostaglandins and thromboxanes. IL-1 can effectthis process by controlling the level of both cyclooxygenase II andinducible nitric oxide synthetase expression (McDaniel et al., 1996,Proc Soc Exp Biol Med. 211, 24).

Inhibitors of cytokine production are expected to block induciblecyclooxygenase (COX-2) expression. COX-2 expression has been shown to beincreased by cytokines and it is believed to be the isoform ofcyclooxygenase responsible for inflammation (M. K. O'Banion et al.,Proc. Natl. Acad. Sci. U.S.A, 1992, 89, 4888.) Accordingly, inhibitorsof cytokines such as IL-1 would be expected to exhibit efficacy againstthose disorders currently treated with COX inhibitors such as thefamiliar NSAIDs. These disorders include acute and chronic pain as wellas symptoms of inflammation and cardiovascular disease,

Elevation of several cytokines have been demonstrated during activeinflammatory bowel disease (IBD). A mucosal imbalance of intestinal IL-1and IL-1ra is present in patients with IBD. Insufficient production ofendogenous IL-1ra may contribute to the pathogenesis of IBD (Cominelli,et al., 1996, Aliment Pharmacol Ther. 10, 49). Alzheimer disease ischaracterized by the presence of beta-amyloid protein deposits,neurofibrillary tangles and cholinergic dysfunction throughout thehippocampal region. The structural and metabolic damage found inAlzheimer disease is possibly due to a sustained elevation ofIL-1(Holden, et al., 1995, Med Hypotheses, 45, 559). A role for IL-1 inthe pathogenesis of human immunodeficiency virus (HIV) has beenidentified. IL-1ra showed a clear relationship to acute inflammatoryevents as well as to the different disease stages in the pathophysiologyof HIV infection (Kreuzer, et al., 1997, Clin Exp Immunol. 109, 54).IL-1 and TNF are both involved in periodontal disease. The destructiveprocess associated with periodontal disease may be due to adisregulation of both IL-1 and TNF (Howells, 1995, Oral Dis. 1, 266).

Proinflammatory cytokines such as TNFα and IL-1β are also importantmediators of septic shock and associated cardiopulmonary dysfunction,acute respiratory distress syndrome (ARDS) and multiple organ failure.TNFα has also been implicated in cachexia and muscle degradation,associated with HIV infection (Lahdiverta et al., 1988, Amer. J. Med.,85, 289). Obesity is associated with an increase incidence of infection,diabetes and cardiovascular disease. Abnormalities in TNFα expressionhave been noted for each of the above conditions (Loffreda, et al.,1998, FASEB J. 12, 57). It has been proposed that elevated levels ofTNFα are involved in other eating related disorders such as anorexia andbulimia nervosa. Pathophysiological parallels are drawn between anorexianervosa and cancer cachexia (Holden, et al., 1996, Med Hypotheses 47,423). An inhibitor of TNFα production, HU-211, was shown to improve theoutcome of closed brain injury in an experimental model (Shohami, etal., 1997, J Neuroimmunol. 72, 169). Atherosclerosis is known to have aninflammatory component and cytokines such as IL-1 and TNF have beensuggested to promote the disease. In an animal model an IL-1 receptorantagonist was shown to inhibit fatty streak formation (Elhage et al.,1998, Circulation, 97, 242).

The abnormal expression of inducible nitric oxide synthetase (iNOS) hasbeen associated with hypertension in the spontaneously hypertensive rat(Chou et al., 1998, Hypertension, 31, 643). IL-1 has a role in theexpression of iNOS and therefore may also have a role in thepathogenesis of hypertension (Singh et al., 1996, Amer. J. Hypertension,9, 867).

IL-1 has also been shown to induce uveitis in rats which could beinhibited with IL-1 blockers. (Xuan et al., 1998, J. Ocular Pharmacol.and Ther., 14, 31). Cytokines including IL-1, TNF and GM-CSF have beenshown to stimulate proliferation of acute myelogenous leukemia blasts(Bruserud, 1996, Leukemia Res. 20, 65). IL-1 was shown to be essentialfor the development of both irritant and allergic contact dermatitis.Epicutaneous sensitization can be prevented by the administration of ananti-IL-1 monoclonal antibody before epicutaneous application of anallergen (Muller, et al., 1996, Am J Contact Dermat. 7, 177). Dataobtained from IL-1 knock out mice indicates the critical involvement infever for this cytokine (Kluger et al., 1998, Clin Exp PharmacolPhysiol. 25, 141). A variety of cytokines including TNF, IL-1, IL-6 andIL-8 initiate the acute-phase reaction which is stereotyped in fever,malaise, myalgia, headaches, cellular hypermetabolism and multipleendocrine and enzyme responses (Beisel, 1995, Am J Clin Nutr. 62, 813).The production of these inflammatory cytokines rapidly follows trauma orpathogenic organism invasion.

Other proinflammatory cytokines have been correlated with a variety ofdisease states. IL-8 correlates with influx of neutrophils into sites ofinflammation or injury. Blocking antibodies against IL-8 havedemonstrated a role for IL-8 in the neutrophil associated tissue injuryin acute inflammation (Harada et al., 1996, Molecular Medicine Today 2,482). Therefore, an inhibitor of IL-8 production may be useful in thetreatment of diseases mediated predominantly by neutrophils such asstroke and myocardial infarction, alone or following thrombolytictherapy, thermal injury, adult respiratory distress syndrome (ARDS),multiple organ injury secondary to trauma, acute glomerulonephritis,dermatoses with acute inflammatory components, acute purulent meningitisor other central nervous system disorders, hemodialysis, leukopherisis,granulocyte transfusion associated syndromes, and necrotizingenterocolitis.

Rhinovirus triggers the production of various proinflammatory cytokines,predominantly IL-8, which results in symptomatic illnesses such as acuterhinitis (Winther et al., 1998, Am J Rhinol 12, 17).

Other diseases that are effected by IL-8 include myocardial ischemia andreperfusion, inflammatory bowel disease and many others.

The proinflammatory cytokine IL-6 has been implicated with the acutephase response. IL-6 is a growth factor in a number in oncologicaldiseases including multiple myeloma and related plasma cell dyscrasias(Treon, et al., 1998, Current Opinion in Hematology 5: 42). It has alsobeen shown to be an important mediator of inflammation within thecentral nervous system. Elevated levels of IL-6 are found in severalneurological disorders including AIDS dementia complex, Alzheimer'sdisease, multiple sclerosis, systemic lupus erythematosus, CNS traumaand viral and bacterial meningitis (Gruol, et al., 1997, MolecularNeurobiology 15: 307). IL-6 also plays a significant role inosteoporosis. In murine models it has been shown to effect boneresorption and to induce osteoclast activity (Ershler et al., 1997,Development and Comparative Immunol. 21: 487). Marked cytokinedifferences, such as IL-6 levels, exist in vivo between osteoclasts ofnormal bone and bone from patients with Paget's disease (Mills, et al.,1997, Calcif Tissue Int. 61, 16). A number of cytokines have been shownto be involved in cancer cachexia. The severity of key parameters ofcachexia can be reduced by treatment with anti IL-6 antibodies or withIL-6 receptor antagonists (Strassmann, et al., 1995, Cytokins Mol Ther.1, 107). Several infectious diseases, such as influenza, indicate IL-6and IFN alpha as key factors in both symptom formation and in hostdefense (Hayden, et al., 1998, J Clin Invest. 101, 643). Overexpressionof IL-6 has been implicated in the pathology of a number of diseasesincluding multiple myeloma, rheumatoid arthritis, Castleman's disease,psoriasis and post-menopausal osteoporosis (Simpson, et al., 1997,Protein Sci. 6, 929). Compounds that interfered with the production ofcytokines including IL-6, and TNF were effective in blocking a passivecutaneous anaphylaxis in mice (Scholz et al., 1998, J. Med. Chem., 41,1050).

GM-CSF is another proinflammatory cytokine with relevance to a number oftherapeutic diseases. It influences not only proliferation anddifferentiation of stem cells but also regulates several other cellsinvolved in acute and chronic inflammation. Treatment with GM-CSF hasbeen attempted in a number of disease states including bum-woundhealing, skin-graft resolution as well as cytostatic and radiotherapyinduced mucositis (Masucci, 1996, Medical Oncology 13: 149). GM-CSF alsoappears to play a role in the replication of human immunodeficiencyvirus (HIV) in cells of macrophage lineage with relevance to AIDStherapy (Crowe et al., 1997, Journal of Leukocyte Biology 62, 41).Bronchial asthma is characterised by an inflammatory process in lungs.Involved cytokines include GM-CSF amongst others (Lee, 1998, J R CollPhysicians Lond 32, 56). Interferon γ (IFNγ) has been implicated in anumber of diseases. It has been associated with increased collagendeposition that is a central histopathological feature ofgraft-versus-host disease (Parkman, 1998, Curr Opin Hematol. 5, 22).Following kidney transplantation, a patient was diagnosed with acutemyelogenous leukemia. Retrospective analysis of peripheral bloodcytokines revealed elevated levels of GM-CSF and IFN γ. These elevatedlevels coincided with a rise in peripheral blood white cell count(Burke, et al., 1995, Leuk Lymphoma. 19, 173). The development ofinsulin-dependent diabetes (Type 1) can be correlated with theaccumulation in pancreatic islet cells of T-cells producing IFN γ(Ablumunits, et al., 1998, J Autoimmun. 11, 73). IFN γ along with TNF,IL-2 and IL-6 lead to the activation of most peripheral T-cells prior tothe development of lesions in the central nervous system for diseasessuch as multiple sclerosis (MS) and AIDS dementia complex (Martino etal., 1998, Ann Neurol. 43, 340). Atherosclerotic lesions result inarterial disease that can lead to cardiac and cerebral infarction. Manyactivated immune cells are present in these lesions, mainly T-cells andmacrophages. These cells produce large amounts of proinflammatorycytokines such as TNF, IL-1 and IFN γ. These cytokines are thought to beinvolved in promoting apoptosis or programmed cell death of thesurrounding vascular smooth muscle cells resulting in theatherosclerotic lesions (Geng, 1997, Heart Vessels Suppl 12, 76).Allergic subjects produce mRNA specific for IFN γ following challengewith Vespula venom (Bonay, et al., 1997, Clin Exp Immunol. 109, 342).The expression of a number of cytokines, including IFN γ has been shownto increase following a delayed type hypersensitivity reaction thusindicating a role for IFN γ in atopic dermatitis (Szepietowski, et al.,1997, Br J Dermatol. 137, 195). Histopathologic and immunohistologicstudies were performed in cases of fatal cerebral malaria. Evidence forelevated IFN γ amongst other cytokines was observed indicating a role inthis disease (Udomsangpetch et al., 1997, Am J Trop Med Hyg. 57, 501).The importance of free radical species in the pathogenesis of variousinfectious diseases has been established. The nitric oxide synthesispathway is activated in response to infection with certain viruses viathe induction of proinflammatory cytokines such as IFN γ (Akaike, etal., 1998, Proc Soc Exp Biol Med. 217, 64). Patients, chronicallyinfected with hepatitis B virus (HBV) can develop cirrhosis andhepatocellular carcinoma. Viral gene expression and replication in HBVtransgenic mice can be suppressed by a post-transcriptional mechanismmediated by IFN γ, TNF and IL-2 (Chisari, et al., 1995, Springer SeminImmunopathol. 17, 261). IFN γ can selectively inhibit cytokine inducedbone resorption. It appears to do this via the intermediacy of nitricoxide (NO) which is an important regulatory molecule in bone remodeling.NO may be involved as a mediator of bone disease for such diseases as:the rheumatoid arthritis, tumor associated osteolysis and postmenopausalosteoporosis (Evans, et al., 1996, J Bone Miner Res. 11, 300). Studieswith gene deficient mice have demonstrated that the IL-12 dependentproduction of IFN γ is critical in the control of early parasiticgrowth. Although this process is independent of nitric oxide the controlof chronic infection does appear to be NO dependent (Alexander et al.,1997, Philos Trans R Soc Lond B Biol Sci 352, 1355). NO is an importantvasodilator and convincing evidence exists for its role incardiovascular shock (Kilbourn, et al., 1997, Dis Mon. 43, 277). IFN γis required for progression of chronic intestinal inflammation in suchdiseases as Crohn's disease and inflammatory bowel disease (IBD)presumably through the intermediacy of CD4+ lymphocytes probably of theTH1 phenotype (Sartor 1996, Aliment Pharmacol Ther. 10 Suppl 2, 43). Anelevated level of serum IgE is associated with various atopic diseasessuch as bronchial asthma and atopic dermatitis. The level of IFN γ wasnegatively correlated with serum IgE suggesting a role for IFN γ inatopic patients (Teramoto et al., 1998, Clin Exp Allergy 28, 74).

Compounds which modulate release of one or more of the aforementionedinflammatory cytokines can be useful in treating diseases associatedwith release of these cytokines. For example, WO 98/52558 disclosesheteroaryl urea compounds which are indicated to be useful in treatingcytokine mediated diseases. WO 99/23091 discloses another class of ureacompounds which are useful as anti-inflammatory agents.

U.S. Pat. No. 5,162,360 discloses N-substituted aryl-N′-heterocyclicsubstituted urea compounds which are described as being useful fortreating hypercholesterolemia and atheroclerosis.

The work cited above supports the principle that inhibition of cytokineproduction will be beneficial in the treatment of various diseasestates. Some protein therapeutics are in late development or have beenapproved for use in particular diseases. Protein therapeutics are costlyto produce and have bioavailability and stability problems. Therefore aneed exists for new small molecule inhibitors of cytokine productionwith optimized efficacy, pharmacokinetic and safety profiles.

BRIEF SUMMARY OF THE INVENTION

In view of the work cited above there is a clear need for compounds thatinhibit cytokine production in order to treat various disease states.

It is therefore an object of the invention to provide novel compoundswhich inhibit the release of inflammatory cytokines such asinterleukin-1 and tumor necrosis factor.

It is a further object of the invention to provide methods for treatingdiseases and pathological conditions involving inflammation such aschronic inflammatory disease, using the novel compounds of theinvention.

It is yet a further object of the invention to provide processes ofpreparation of the above-mentioned novel compounds.

DETAILED DESCRIPTION OF THE INVENTION

In one generic aspect of the invention, there is provided compounds ofthe formula(I):

wherein:

Ar₁ is selected from the group consisting of:

pyrrole, pyrrolidine, pyrazole, imidazole, oxazole, thiazole, furan andthiophene; wherein Ar₁ may be substituted by one or more R₁, R₂ or R₃;

Ar₂ is:

phenyl, naphthyl, quinoline, isoquinoline, tetrahydronaphthyl,tetrahydroquinoline, tetrahydroisoquinoline, benzimidazole, benzofuran,indanyl, indenyl or indole each being optionally substituted with zeroto three R₂ groups;

X is:

a) a C₅₋₈ cycloalkyl or cycloalkenyl optionally substituted with 0-2 oxogroups or 0-3 C₁₋₄ branched or unbranched alkyl, C₁₋₄ alkoxy or C₁₋₄alkylamino chains;

b) phenyl, furan, thiophene, pyrrole, imidazolyl, pyridine, pyrimidine,pyridinone, dihydropyridinone, maleimide, dihydromaleimide, piperdine,piperazine or pyrazine each being optionally independently substitutedwith 0-3 C₁₋₄ branched or unbranched alkyl, C₁₋₄alkoxy, hydroxy,nitrile, mono- or di-(C₁₋₃ alkyl)amino, C₁₋₆ alkyl-S(O)_(m), or halogen;

Y is:

a bond or a C₁₋₄ saturated or unsaturated branched or unbranched carbonchain optionally partially or fully halogenated, wherein one or moremethylene groups are optionally replaced by O, NH, S(O), S(O)₂ or S andwherein Y is optionally independently substituted with 0-2 oxo groupsand one or more C₁₋₄ branched or unbranched alkyl which may besubstituted by one or more halogen atoms;

Z is:

a) phenyl, pyridine, pyrimidine, pyridazine, imidazole, furan,thiophene, pyran, which are optionally substituted with one to threegroups consisting of halogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, hydroxy, mono- ordi-(C₁₋₃ alkyl)amino, C₁₋₆ alkyl-S(O)_(m), COOH and phenylamino whereinthe phenyl ring is optionally substituted with one to two groupsconsisting of halogen, C₁₋₆ alkyl and C₁₋₆ alkoxy;

b) tetrahydropyran, tetrahydrofuran, 1,3-dioxolanone, 1,3-dioxanone,1,4-dioxane, morpholine, thiomorpholine, thiomorpholine sulfoxide,piperidine, piperidinone, piperazine, tetrahydropyrimidone,cyclohexanone, cyclohexanol, pentamethylene sulfide, pentamethylenesulfoxide, pentamethylene sulfone, tetramethylene sulfide,tetramethylene sulfoxide or tetramethylene sulfone which are optionallysubstituted with one to three groups consisting of nitrile, C₁₋₆ alkyl,C₁₋₆ alkoxy, hydroxy, mono- or di-(C₁₋₃ alkyl)amino-C₁₋₃ alkyl,phenylamino-C₁₋₃ alkyl and C₁₋₃ alkoxy-C₁₋₃ alkyl;

c) C₁₋₆ alkoxy, secondary or tertiary amine wherein the amino nitrogenis covalently bonded to groups selected from the group consisting ofC₁₋₃ alkyl, C₁₋₅ alkoxyalkyl, pyridinyl-C₁₋₃ alkyl, imidazolyl-C₁₋₃alkyl, tetrahydrofuranyl-C₁₋₃ alkyl, phenylamino, wherein the phenylring is optionally substituted with one to two halogen, C₁₋₆ alkoxy,hydroxy or mono- or di-(C₁₋₃ alkyl)amino, C₁₋₆ alkyl-S(O)_(m), andphenyl-S(O)_(m), wherein the phenyl ring is optionally substituted withone to two halogen, C₁₋₆ alkoxy, hydroxy or mono- or di-(C₁₋₃alkyl)amino;

R₁ is:

(a) C₃₋₁₀ branched or unbranched alkyl optionally partially or fullyhalogenated and optionally substituted with one to three phenyl,naphthyl or heterocyclic groups selected from the group consisting ofpyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl,pyrazolyl, thienyl, furyl, isoxazolyl and isothiazolyl; each suchphenyl, naphthyl or heterocycle selected from the group hereinabovedescribed in this paragraph, and being substituted with 0 to 5 groupsselected from the group consisting of halogen, C₁₋₆ branched orunbranched alkyl which is optionally partially or fully halogenated,C₃₋₈ cycloalkyl, C₅₋₈ cycloalkenyl, hydroxy, nitrile, C₁₋₃ alkyloxywhich is optionally partially or fully halogenated, NH₂C(O) anddi(C₁₋₃)alkylaminocarbonyl;

(b) C₃₋₇ cycloalkyl selected from the group consisting of cyclopropyl,cyclobutyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl,bicyclohexanyl and bicycloheptanyl each being optionally be partially orfully halogenated and optionally substituted with one to three C₁₋₃alkyl groups, or an analog of such cycloalkyl group wherein one to threering methylene groups are replaced by groups independently selected fromthe group consisting of O, S, CHOH,>C═O,>C═S and NH;

(c) C₃₋₁₀ branched alkenyl optionally partially or fully halogenated andoptionally substituted with one to three C₁₋₅ branched or unbranchedalkyl, phenyl, naphthyl or heterocyclic groups, with each suchheterocyclic group being independently selected from the groupconsisting of pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl,imidazolyl, pyrazolyl, thienyl, furyl, isoxazolyl and isothiazolyl, andeach such phenyl, naphthyl or heterocyclic group being substituted with0 to 5 groups selected from the group consisting of halogen, C₁₋₆branched or unbranched alkyl which is optionally partially or fullyhalogenated, cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl,cycloheptanyl, bicyclopentanyl, bicyclohexanyl, bicycloheptanyl,hydroxy, nitrile, C₁₋₃ alkoxy which is optionally partially or fullyhalogenated, NH₂C(O) and mono- or di(C₁₋₃)alkylaminocarbonyl;

(d) a C₅₋₇ cycloalkenyl selected from the group consisting ofcyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl,cycloheptadienyl, bicyclohexenyl and bicycloheptenyl, wherein suchcycloalkenyl group is optionally substituted with one to three C₁₋₃alkyl groups;

(e) nitrile; or

(f) C₁₋₆ branched or unbranched alkoxycarbonyl, C₁₋₆ branched orunbranched alkylaminocarbonyl, C₁₋₆ branched or unbranchedalkylcarbonylamino-C₁₋₃-alkyl;

R₂ is:

a C₁₋₆ branched or unbranched alkyl optionally partially or fullyhalogenated, acetyl, aroyl, C₁₋₄ branched or unbranched alkoxyoptionally partially or fully halogenated, halogen, methoxycarbonyl orphenylsulfonyl;

R₃ is:

a) phenyl, naphthyl or heterocyclic group selected from the groupconsisting of pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl,imidazolyl, pyrazolyl, thienyl, furyl, tetrahydrofuryl, isoxazolyl,isothiazolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl,benzofuranyl, benzoxazolyl, benzisoxazolyl, benzpyrazolyl,benzothiofuranyl, cinnolinyl, pterindinyl, phthalazinyl,naphthypyridinyl, quinoxalinyl, quinazolinyl, purinyl and indazolyl,wherein such phenyl, naphthyl or heterocyclic group is optionallysubstituted with one to five groups selected from the group consistingof phenyl, naphthyl, heterocycle selected from the group hereinabovedescribed in this paragraph, C₁₋₆ branched or unbranched alkyl which isoptionally partially or fully halogenated, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, bicyclopentyl, bicyclohexyl,bicycloheptyl, phenyl C₁₋₅ alkyl, naphthyl C₁₋₅ alkyl, halogen, hydroxy,nitrile, C₁₋₃ alkyloxy which may optionally be partially or fullyhalogenated, phenyloxy, naphthyloxy, heteraryloxy wherein theheterocyclic moiety is selected from the group hereinabove described inthis paragraph, nitro, amino, mono- or di-(C₁₋₃)alkylamino, phenylamino,naphthylamino, heterocyclylamino wherein the heterocyclyl moiety isselected from the group hereinabove described in this paragraph,NH₂C(O), a mono- or di-(C₁₋₃)alkyl aminocarbonyl, C₁₋₅ alkyl-C(O)—C₁₋₄alkyl, amino-C₁₋₅ alkyl, mono- or di-(C₁₋₃)alkylamino-C₁₋₅ alkyl,amino-S(O)₂, di-(C₁₋₃)alkylamino-S(O)₂, R₄ —C₁₋₅ alkyl, R₅—C₁₋₅ alkoxy,R₆—C(O)—C₁₋₅ alkyl and R₇—C₁₋₅ alkyl(R₈)N, carboxy-mono- ordi-(C₁₋₅)-alkyl-amino;

b) a fused aryl selected from the group consisting of benzocyclobutanyl,indanyl, indenyl, dihydronaphthyl, tetrahydronaphthyl,benzocycloheptanyl and benzocycloheptenyl, or a fused heterocyclylselected from the group consisting of cyclopentenopyridine,cyclohexanopyridine, cyclopentanopyrimidine, cyclohexanopyrimidine,cyclopentanopyrazine, cyclohexanopyrazine, cyclopentanopyridazine,cyclohexanopyridazine, cyclopentanoquinoline, cyclohexanoquinoline,cyclopentanoisoquinoline, cyclohexanoisoquinoline, cyclopentanoindole,cyclohexanoindole, cyclopentanobenzimidazole, cyclohexanobenzimidazole,cyclopentanobenzoxazole, cyclohexanobenzoxazole, cyclopentanoimidazole,cyclohexanoimidazole, cyclopentanothiophene and cyclohexanothiophene;wherein the fused aryl or fused heterocyclyl ring is substituted with 0to 3 groups independently selected from the group consisting of phenyl,naphthyl and heterocyclyl selected from the group consisting ofpyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl,pyrazolyl, thienyl, furyl, isoxazolyl, and isothiazolyl, C₁₋₆ branchedor unbranched alkyl which is optionally partially or fully halogenated,halogen, nitrile, C₁₋₃ alkoxy which is optionally partially or fullyhalogenated, phenyloxy, naphthyloxy, heterocyclyloxy wherein theheterocyclyl moiety is selected from the group hereinabove described inthis paragraph, nitro, amino, mono- or di-(C₁₋₃)alkylamino, phenylamino,naphthylamino, heterocyclylamino wherein the heterocyclyl moiety isselected from the group hereinabove described in this paragraph,NH₂C(O), a mono- or di-(C₁₋₃)alkyl aminocarbonyl, C₁₋₄ alkyl-OC(O), C₁₋₅alkyl-C(O)—C₁₋₄ branched or unbranched alkyl, an amino-C₁₋₅ alkyl, mono-or di-(C₁₋₃)alkylamino-C₁₋₅ alkyl, R₉—C₁₋₅ alkyl, R₁₀—C₁₋₅ alkoxy,R₁₁—C(O)—C₁₋₅ alkyl, and R₁₂—C₁₋₅ alkyl(R₁₃)N;

c) cycloalkyl selected from the group consisting of cyclopentyl,cyclohexyl, cycloheptyl, bicyclopentyl, bicyclohexyl and bicycloheptyl,wherein the cycloalkyl is optionally partially or fully halogenated andoptionally substituted with one to three C₁₋₃ alkyl groups;

d) C₅₋₇ cycloalkenyl selected from the group consisting ofcyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl,cycloheptadienyl, bicyclohexenyl and bicycloheptenyl, wherein suchcycloalkenyl group is optionally substituted with one to three C₁₋₃alkyl groups;

e) acetyl, aroyl, alkoxycarbonylalkyl or phenylsulfonyl; or

f) C₁₋₆ branched or unbranched alkyl optionally partially or fullyhalogenated; or R₁ and R₂ taken together may optionally form a fusedphenyl or pyridinyl ring;

each R₈ and R₁₃ is independently selected from the group consisting of:hydrogen and C₁₋₄ branched or unbranched alkyl optionally be partiallyor fully halogenated;

each R₄, R₅, R₆, R₇, R₉, R₁₀, R₁₁ and R₁₂ is independently selected fromthe group consisting of morpholine, piperidine, piperazine, imidazoleand tetrazole;

m is 0, 1 or 2;

W is O or S and

pharmaceutically acceptable derivatives thereof.

In one embodiment of the invention there are compounds of the formula(I)as provided above and wherein:

Ar₂ is naphthyl, tetrahydronaphthyl, indanyl or indenyl and W is O.

In another embodiment of the invention, there are the compounds of theformula (I) as provided immediately above and wherein:

Ar₁ is selected from thiophene and pyrazole;

X is C₅₋₇ cycloalkyl or C₅₋₇cycloalkenyl optionally substituted with 0-2oxo groups or 0-3 C₁₋₄ branched or unbranched alkyl, C₁₋₄ alkoxy or C₁₋₄alkylamino; or X is phenyl, pyridine, tetrahydropyridine, pyrimidine,furan or thiophene each being optionally independently substituted with0-3 C₁₋₄ branched or unbranched alkyl, C₁₋₄alkoxy, hydroxy, nitrile,mono- or di-(C₁₋₃ alkyl)amino, C₁₋₆ alkyl-S(O)_(m) or halogen;

R₁ is C₁₋₄alkyl branched or unbranched, cyclopropyl or cyclohexyloptionally partially or fully halogenated and optionally substitutedwith one to three C₁₋₃alkyl groups;

R₃ is C₁₋₄alkyl branched or unbranched, phenyl, pyrimidinyl, pyrazolylor pyridinyl each being optionally substituted as described hereinabovein the broadest generic aspect, alkoxycarbonylalkyl or cyclopropyl orcyclopentyl optionally substituted as described hereinabove in thebroadest generic aspect.

In yet another embodiment of the invention are the compounds of theformula(I) as provided immediately above and wherein:

Ar₁ is pyrazole;

X is cyclopentenyl, cyclohexenyl or cycloheptenyl, optionallysubstituted with an oxo group or 0-3 C₁₋₄ branched or unbranched alkyl,C₁₋₄alkoxy or C₁₋₄alkylamino; or X is phenyl, pyridine, furan orthiophene each being optionally independently substituted with 0-3 C₁₋₄branched or unbranched alkyl, C₁₋₄alkoxy, hydroxy, nitrile, mono- ordi-(C₁₋₃ alkyl)amino, C₁₋₆ alkyl-S(O)_(m) or halogen.

In yet still another embodiment of the invention there the compounds ofthe formula(I) as provided immediately above and wherein:

Y is —CH2—, —CH2CH2—, —CH2NH—, —CH2CH2NH— or a bond;

and

Z is

phenyl, imidazole, furan, piperazine, tetrahydropyran, morpholine,thiomorpholine, thiomorpholine sulfoxide, piperidine, pyridine,secondary or tertiary amine wherein the amino nitrogen is covalentlybonded to groups selected from the group consisting of C₁₋₃ alkyl andC₁₋₅ alkoxyalkyl, phenylamino wherein the phenyl ring is optionallysubstituted with one to two halogen, C₁₋₆ alkoxy, hydroxy or mono- ordi-(C₁₋₃ alkyl)amino, C₁₋₆ alkyl-S(O)_(m) and phenyl-S(O)_(m) whereinthe phenyl ring is optionally substituted with one to two halogen, C₁₋₆alkoxy, hydroxy or mono- or di-(C₁₋₃ alkyl)amino.

In yet a further embodiment of the invention there are the compounds ofthe formula(I) as provided immediately above and wherein:

Ar₁ is 5-tert-butyl-pyrazol-3-yl; wherein the pyrazole ring may besubstituted by R₃;

R₃ is C₁₋₄alkyl branched or unbranched, phenyl, pyrimidinyl, pyrazolyl,pyridinyl each being optionally substituted as described hereinabove inthe broadest generic aspect, alkoxycarbonylalkyl or cyclopropyl orcyclopentyl optionally substituted as described hereinabove in thebroadest generic aspect.

In a still yet further embodiment of the invention there are thecompounds of the formula(I) as provided immediately above and wherein Xis pyridinyl.

In yet another further embodiment of the invention there are thecompounds of the formula(I) as provided immediately above and whereinthe pyridinyl is attached to Ar₁ via the 3-pyridinyl position.

The following are representative compounds of formula(I) of theinvention:

1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(4-(morpholin-4-yl)phenyl)naphthal-1-yl]urea;

1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(4-(morpholin-4-yl-methl)phenyl)naphthalen-1-yl]urea;

1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(4-(2-(morpholin-4-yl)ethyl)phenyl)naphthalen-1-yl]urea;

1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(4-dimethylaminophenyl)naphthalen-1-yl]urea;

1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(3-(morpholin-4-yl)phenyl)naphthalen-1-yl]urea;

1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(3-(morpholin-4-yl-methyl)phenyl)naphthalen-1-yl]urea;

1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(6-morpholin-4-ylmethyl-pyridin-2-yl)naphthalen-1-yl]urea;

1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(5-morpholin-4-ylmethyl-pyridin-1-yl)naphthalen-1-yl]urea;

1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(5-morpholin-4-ylmethyl-pyridin-4-yl)naphthalen-1-yl]urea;

1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)naphthalen-1-yl]urea;

1-[5-tert-butyl-2-methyl-2H-pyrazol-3-yl]-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)naphthalen-1-yl]urea;

1-[5-tert-butyl-2-phenyl-2H-pyrazol-3-yl]-3-[4-(4-piperdin-1-ylmethyl-phenyl)naphthalen-1-yl]urea;

1-[5-tert-butyl-2-phenyl-2H-pyrazol-3-yl]-3-[4-(4-(4-methylpiperazin-1-yl)methylphenyl)naphthalen-1-yl]urea;

1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(3,4-di(morpholin-4-yl-methyl)phenyl)naphthalen1-yl]urea;

1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-pyridin-4-ylmethyl-pyridin-3-yl)naphthalen-1-yl]urea;

1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-(1-oxo-thiomorpholin-4-ylmethyl)pyridin-3-yl)naphthalen-1-yl]urea;

1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(6-(1-oxo-thiomorpholin-4-ylmethyl)pyridin-3-yl)naphthalen-1-yl]urea;

1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-tetrahydropholin-4-ylmethyl-pyridin-3-yl)naphthalen-1-yl]urea;

1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-(1-oxo-tetrahydrothiophen-3-ylmethyl)pyridin-3-yl)naphthalen-1-yl]urea;

1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-(imidazol-1-ylmethyl)pyridin-3-yl)naphthalen-1-yl]urea;

1-[2-(3-dimethylaminomethylphenyl)-5-(1-methyl-cyclohexyl)-2H-pyrazol-3-yl]-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)naphthalen-1-yl]urea;

1-[2-(5-(1-methyl-cyclohexyl)-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)naphthalen-1-yl]urea;

1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-morpholin-4-ylmethyl-pyrimidin-5-yl)naphthalen-1-yl]urea;

1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(3-methoxy-5-(2-morpholin-4-yl-ethoxy)phenyl)naphthalen-1-yl]urea;

1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(3-(2-morpholin-4-ethoxy)phenyl)naphthalen-1-yl]urea;

1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-3-(dimethylamino)phenyl)naphthalen-1-yl]urea;

1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-3-(methylsulfonyl)phenyl)naphthalen-1-yl]urea;

5-tert-butyl-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)naphthalen-1-yl]ureido}thiophene-2-carboxylicacid methyl ester;

5-tert-butyl-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)naphthalen-1-yl]ureido}thiophene-2-carboxylicacid methylamide;

5-tert-butyl-1-methyl-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)naphthalen-1-yl]ureido}-1H-pyrrole-2-carboxylicacid methyl ester;

5-tert-butyl-1-methyl-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)naphthalen-1-yl]ureido}-1H-pyrrole-2-carboxylicacid methylamide;

2-acetylaminoN-(5-tert-butyl-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)naphthalen-1-yl]ureido}thiophen-2-ylmethyl)acetamide;

1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(3-morpholin-4-yl-cyclohex-1-enyl)naphthalen-1-yl]urea;

1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(3-morpholin-4-yl-cylohept-1-enyl)naphthalen-1-yl]urea;

1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(3-(2-morpholin-4-yl-ethylamion)cyclohex-1-enyl)naphthalen-1-yl]urea;

1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(3-morpholin-4-yl-cyclohept-1-enyl)naphthalen-1-yl]urea;

1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(3-(pyridin-4-methylamino)cyclohex-1-enyl)naphthalen-1-yl]urea;

1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(3-(dimethylaminoethylamino)cyclohex-1-enyl)naphthalen-1-yl]urea;

1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(3-(phenyl-methylamino)cyclohex-1-enyl)naphthalen-1-yl]urea;

1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(3-(phenyl-methylamino)cyclohex-1-enyl)naphthalen-1-yl]urea;

1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(3-(2-phenylethylamino)cyclohex-1-enyl)naphthalen-1-yl]urea;

1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(3-(furan-2-yl-methylamino)cyclohex-1-enyl)naphthalen-1-yl]urea;

1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(3-(2-pyridin-2-ethylamino)cyclohex-1-enyl)naphthalen-1-yl]urea;

1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(3-(2-pyridin-1-yl-ethylamino)cyclohex-1-enyl)naphthalen-1-yl]urea;

1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(3-(2-imidazol-4-yl-ethylamino)cyclohex-1-enyl)naphthalen-1-yl]urea;

1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(3-(pyridin-2-yl-methylamino)cyclohex-1-enyl)naphthalen-1-yl]urea;

1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(3-(2-(4-methoxyphenyl)ethylamino)cyclohex-1-enyl)naphthalen-1-yl]urea;

1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(4-morpholin-4-ylmethyl-3-oxo-cyclohex-1-enyl)naphthalen-1-yl]urea;

1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(4-(1-oxo-tetrahydrothiophen-3-ylmethyl)-3-oxo-cyclohex-1-enyl)naphthalen-1-yl]urea;

1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(4-(1-oxo-thiomorpholin-4-ylmethyl)-3-oxo-cyclohex-1-enyl)naphthalen-1-yl]urea;

1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(4-methylpiperazin-1-ylmethyl)-3-oxo-cyclohex-1-enyl)naphthalen-1-yl]urea;

1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-{6-oxo-1-(tetrahydro-pyran-4-ylmethyl)-1,2,3,6-tetrahydro-pyridin-4-yl}naphthalen-1-yl]urea;

1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(2-oxo-1-pyridin-4-ylmethyl-piperdin-4-yl)naphthalen-1-yl]urea;

1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(6-oxo-1-pyridin-4-yl-1,2,3,6,-pyridin-4-yl)naphthalen-1-yl]urea;

1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-oxo-1-pyridin-4-1,2,3,6-tetrahydro-pyridin-4-yl)naphthalen-1-yl]urea;

5-tert-butyl-3-{3-[4-(6-oxo-1-pyridin-4-yl-1,2,3,6-tetrahydro-pyridin-4-yl)naphthalen-1-yl]ureido}thiophene-2-carboxylicacid methyl ester;

5-tert-butyl-1-methyl-3-{3-[4-(6-oxo-1-pyridin-4-yl-1,2,3,6-tetrahydro-pyridin-4-yl)naphthalen-1-yl]ureido}pyrrole-2-carboxylicacid methyl ester;

5-tert-butyl-1-methyl-3-{3-[4-(6-oxo-1-pyridin-4-yl-1,2,3,6-tetrahydro-pyridin-4-yl)naphthalen-1-yl]ureido}pyrrole-2-carboxylicacid methyl amide;

5-tert-butyl-3-{3-[4-(3-morpholin-4-yl-cyclohex-1-enyl)naphthalen-1-yl]ureido}thiophene-2-carboxylicacid methyl ester;

5-tert-butyl-1-methyl-3-{3-[4-(3-morpholin-4-yl-cyclohex-1-enyl)naphthalen-1-yl]ureido}pyrrole-2-carboxylicacid methyl ester; and

5-tert-butyl-1-methyl-3-{3-[4-(3-morpholin-4-yl-cyclohex-1-enyl)naphthalen-1-yl]ureido}pyrrole-2-carboxylicacid methyl amide and the pharmaceutically acceptable derivativesthereof.

In another embodiment of the invention there are provided the followingcompounds of formula(I):

1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(4-(morpholin-4-yl-methyl)phenyl)naphthalen-1-yl]urea;

1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(4-(2-(morpholin-4-yl)ethyl)phenyl)naphthalen-1-yl]urea;

1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(3-(morpholin-4-yl-methyl)phenyl)naphthalen-1-yl]urea;

1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)naphthalen-1-yl]urea;

1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(5-morpholin-4-ylmethyl-pridin-2-yl)naphthalen-1-yl]urea;

1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(5-morpholin-4-ylmethyl-fur-2-yl)naphthalen-1-yl]urea;

1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)naphthalen-1-yl]urea;

1-[5-tert-butyl-2-methyl-2H-pyrazol-3-yl]-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)naphthalen-1-yl]ureaand the pharmaceutically acceptable derivatives thereof.

In another generic aspect of the invention, there are provided compoundsof the formula (Ia):

wherein:

Ar₁ is:

pyrrole, pyrrolidine, pyrazole, imidazole, oxazole, thiazole, furan andthiophene;

wherein Ar₁ is optionally substituted by one or more R₁, R₂ or R₃;

Ar₂ is:

phenyl, naphthyl, quinoline, isoquinoline, tetrahydronaphthyl,tetrahydroquinoline, tetrahydroisoquinoline, benzimidazole, benzofuran,indanyl, indenyl and indole each being optionally substituted with zeroto three R₂ groups;

X is:

a C₅₋₈ cycloalkyl or cycloalkenyl optionally substituted with one to twooxo groups or one to three C₁₋₄ alkyl, C₁₋₄ alkoxy or C₁₋₄ alkylaminochains each being branched or unbranched;

phenyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, pyridinyl,tetrahydropyridinyl, pyrimidinyl, pyridinonyl, dihydropyridinonyl,maleimidyl, dihydromaleimidyl, piperdinyl, benzimidazole,3H-imidazo[4,5-b]pyridine, piperazinyl, pyridazinyl or pyrazinyl; eachbeing optionally independently substituted with one to three C₁₋₄ alkyl,C₁₋₄alkoxy, hydroxy, nitrile, amino, mono- or di-(C₁₋₃ alkyl)amino,mono- or di-(C₁₋₃ alkylamino)carbonyl, NH₂C(O), C₁₋₆ alkyl-S(O)_(m) orhalogen;

Y is:

a bond or a C₁₋₄ saturated or unsaturated branched or unbranched carbonchain optionally partially or fully halogenated, wherein one or more Catoms are optionally replaced by O, N, or S(O)_(m) and wherein Y isoptionally independently substituted with one to two oxo groups,nitrile, phenyl, hydroxy or one or more C₁₋₄ alkyl optionallysubstituted by one or more halogen atoms;

Z is:

aryl, indanyl, heteroaryl selected from benzimidazolyl, pyridinyl,pyrimidinyl, pyridazinyl, pyrazinyl, imidazolyl, pyrazolyl, triazolyl,tetrazolyl, furanyl, thienyl and pyranyl, heterocycle selected frompiperazinyl, tetrahydropyrimidonyl, cyclohexanonyl, cyclohexanolyl,2-oxa- or 2-thia-5-aza-bicyclo[2.2.1]heptanyl, pentamethylene sulfidyl,pentamethylene sulfoxidyl, pentamethylene sulfonyl, tetramethylenesulfidyl, tetramethylene sulfoxidyl or tetramethylene sulfonyl,tetrahydropyranyl, tetrahydrofuranyl, 1,3-dioxolanonyl, 1,3-dioxanonyl,1,4-dioxanyl, morpholino, thiomorpholino, thiomorpholino sulfoxidyl,thiomorpholino sulfonyl, piperidinyl, piperidinonyl, pyrrolidinyl anddioxolanyl,

each of the aforementioned Z are optionally substituted with one tothree halogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₃ alkoxy-C₁₋₃ alkyl, C₁₋₆alkoxycarbonyl, aroyl, heteroaroyl, heterocycleC₁₋₃acyl wherein theheteroaryl and heterocycle are as defined hereinabove in this paragraph,C₁₋₃acyl, oxo, hydroxy, pyridinyl-C₁₋₃ alkyl, imidazolyl-C₁₋₃ alkyl,tetrahydrofuranyl-C₁₋₃ alkyl, nitrile-C₁₋₃ alkyl, nitrile, carboxy,phenyl wherein the phenyl ring is optionally substituted with one to twohalogen, C₁₋₆ alkoxy, hydroxy or mono- or di-(C₁₋₃ alkyl)amino,amino-S(O)_(m), C₁₋₆ alkyl-S(O)_(m) or phenyl-S(O)_(m) wherein thephenyl ring is optionally substituted with one to two halogen, C₁₋₆alkoxy, hydroxy, halogen or mono- or di-(C₁₋₃ alkyl)amino;

or Z is optionally substituted with one to three amino, aminocarbonyl oramino-C₁₋₃ alkyl wherein the N atom is optionally independently mono- ordi-substituted by aminoC₁₋₆ alkyl, C₁₋₃ alkyl, arylC₀₋₃ alkyl, C₁₋₅alkoxyC₁₋₃ alkyl, C₁₋₅ alkoxy, aroyl, C₁₋₃acyl, C₁₋₃ alkyl-S(O)_(m)— orarylC₀₋₃ alkyl-S(O)_(m)— each of the aforementioned alkyl and arylattached to the amino group is optionally substituted with one to twohalogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, hydroxy or mono- or di-(C₁₋₃alkyl)amino;

or Z is optionally substituted with one to three aryl, heterocycle orheteroaryl as hereinabove described in this paragraph each in turn isoptionally substituted by halogen, C₁₋₆ alkyl or C₁₋₆ alkoxy;

or Z is hydroxy, hydroxyC₁₋₃ alkyl, halogen, nitrile, amino wherein theN atom is optionally independently mono- or di-substituted by C₁₋₆alkyl, aminoC₁₋₆ alkyl, arylC₀₋₃ alkyl, C₁₋₅ alkoxyC₁₋₃ alkyl, C₁₋₅alkoxy, aroyl, C₁₋₃acyl, C₁₋₃ alkyl-S(O)_(m)-, arylC₀₋₃ alkyl-S(O)_(m)-,nitrileC₁₋₄ alkyl or C₁₋₃alkoxyC₁₋₃ alkyl, each of the aforementionedalkyl and aryl attached to the amino group is optionally substitutedwith one to two halogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, hydroxy or mono- ordi-(C₁₋₃ alkyl)amino, C₁₋₆ alkoxyheteroarylC₀₋₃ alkyl, heteroarylC₀₋₃alkyl or heterocycyleC₀₋₃ alkyl wherein the heteroaryl and heterocycleis hereinabove described in this paragraph,

or Z is C₁₋₆ alkyl branched or unbranched, C₁₋₆alkoxy, C₁₋₃acylamino,nitrileC₁₋₄ alkyl, C₁₋₆ alkyl-S(O)_(m), and phenyl-S(O)_(m), wherein thephenyl ring is optionally substituted with one to two halogen, C₁₋₆alkoxy, hydroxy or mono- or di-(C₁₋₃ alkyl)amino;

R₁ is:

a) C₁₋₁₀ branched or unbranched alkyl optionally partially or fullyhalogenated, and optionally substituted with one to three phenyl,naphthyl or heterocyclic groups selected from the group consisting ofpyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl,pyrazolyl, thienyl, furyl, isoxazolyl and isothiazolyl; each suchphenyl, naphthyl or heterocycle, selected from the group hereinabovedescribed, being substituted with 0 to 5 groups selected from the groupconsisting of halogen, C₁₋₆ branched or unbranched alkyl which isoptionally partially or fully halogenated, C₃₋₈ cycloalkyl, C₅₋₈cycloalkenyl, hydroxy, nitrile, C₁₋₃ alkyloxy which is optionallypartially or fully halogenated, NH₂C(O) and di(C₁₋₃)alkylaminocarbonyl;

b) C₃₋₇ cycloalkyl selected from the group consisting of cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclopentyl,bicyclohexyl and bicycloheptyl, each optionally partially or fullyhalogenated and optionally substituted with one to three C₁₋₃ alkylgroups, or an analog of such cycloalkyl group wherein one to three ringmethylene groups are replaced by groups independently selected from thegroup consisting of O, S, CHOH,>C═O,>C═S and NH;

c) C₃₋₁₀ branched alkenyl optionally partially or fully halogenated andoptionally substituted with one to three C₁₋₅ branched or unbranchedalkyl, phenyl, naphthyl or heterocyclic groups, with each suchheterocyclic group being independently selected from the groupconsisting of pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl,imidazolyl, pyrazolyl, thienyl, furyl, isoxazolyl and isothiazolyl, andeach such phenyl, naphthyl or heterocyclic group being substituted with0 to 5 groups selected from the group consisting of halogen, C₁₋₆branched or unbranched alkyl which is optionally partially or fullyhalogenated, cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl,cycloheptanyl, bicyclopentanyl, bicyclohexanyl, bicycloheptanyl,hydroxy, nitrile, C₁₋₃ alkoxy which is optionally partially or fullyhalogenated, NH₂C(O) and mono- or di(C₁₋₃)alkylaminocarbonyl;

d) a C₅₋₇ cycloalkenyl selected from the group consisting ofcyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl,cycloheptadienyl, bicyclohexenyl and bicycloheptenyl, wherein suchcycloalkenyl group is optionally substituted with one to three C₁₋₃alkyl groups;

e) nitrile; or

f) C₁₋₆ branched or unbranched alkoxycarbonyl, C₁₋₆ branched orunbranched alkylaminocarbonyl, C₁₋₆ branched or unbranchedalkylcarbonylamino-C₁₋₃-alkyl;

R₂ is:

a C₁₋₆ branched or unbranched alkyl optionally partially or fullyhalogenated and optionally substituted with nitrile,

or R₂ is acetyl, aroyl, C₁₋₄ branched or unbranched alkoxy optionallypartially or fully halogenated, halogen, methoxycarbonyl orphenylsulfonyl;

R₃ is:

a) phenyl, naphthyl or heterocyclic group selected from the groupconsisting of pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl,imidazolyl, pyrazolyl, thienyl, furyl, tetrahydrofuryl, isoxazolyl,isothiazolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl,benzofuranyl, benzoxazolyl, benzisoxazolyl, benzpyrazolyl,benzothiofuranyl, cinnolinyl, pterindinyl, phthalazinyl,naphthypyridinyl, quinoxalinyl, quinazolinyl, purinyl and indazolyl,wherein such phenyl, naphthyl or heterocyclic group is optionallysubstituted with one to five groups selected from the group consistingof a phenyl, naphthyl, heterocycle selected from the group hereinabovedescribed in this paragraph, C₁₋₆ branched or unbranched alkyl which isoptionally partially or fully halogenated, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, bicyclopentyl, bicyclohexyl,bicycloheptyl, phenyl C₁₋₅ alkyl, naphthyl C₁₋₅ alkyl, halogen, hydroxy,oxo, nitrile, C₁₋₃ alkoxy optionally partially or fully halogenated,C₁₋₃ alkoxyC₁₋₅ alkyl, C₁₋₃thioalkyl, C₁₋₃thioalkylC₁₋₅ alkyl,phenyloxy, naphthyloxy, heteraryloxy wherein the heterocyclic moiety isselected from the group hereinabove described in this paragraph, nitro,amino, mono- or di-(C₁₋₃)alkylamino, phenylamino, naphthylamino,heterocyclylamino wherein the heterocyclyl moiety is selected from thegroup hereinabove described in this paragraph, NH₂C(O), a mono- ordi-(C₁₋₃)alkyl aminocarbonyl, C₁₋₅ alkyl-C(O)—C₁₋₄ alkyl, amino-C₁₋₅alkyl, mono- or di-(C₁₋₃)alkylamino-C₁₋₅ alkyl, amino-S(O)₂,di-(C₁₋₃)alkylamino-S(O)₂, R₄—C₁₋₅ alkyl, R₅—C₁₋₅alkoxy, R₆—C(O)—C₁₋₅alkyl and R₇—C₁₋₅ alkyl(R₈)N, carboxy-mono- or di-(C₁₋₅)-alkyl-amino;

b) a fused aryl selected from the group consisting of benzocyclobutanyl,indanyl, indenyl, dihydronaphthyl, tetrahydronaphthyl,benzocycloheptanyl and benzocycloheptenyl, or a fused heterocyclylselected from the group consisting of cyclopentenopyridine,cyclohexanopyridine, cyclopentanopyrimidine, cyclohexanopyrimidine,cyclopentanopyrazine, cyclohexanopyrazine, cyclopentanopyridazine,cyclohexanopyridazine, cyclopentanoquinoline, cyclohexanoquinoline,cyclopentanoisoquinoline, cyclohexanoisoquinoline, cyclopentanoindole,cyclohexanoindole, cyclopentanobenzimidazole, cyclohexanobenzimidazole,cyclopentanobenzoxazole, cyclohexanobenzoxazole, cyclopentanoimidazole,cyclohexanoimidazole, cyclopentanothiophene and cyclohexanothiophene;wherein the fused aryl or fused heterocyclyl ring is substituted with 0to 3 groups independently selected from the group consisting of phenyl,naphthyl and heterocyclyl selected from the group consisting ofpyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl,pyrazolyl, thienyl, furyl, isoxazolyl, and isothiazolyl, C₁₋₆ branchedor unbranched alkyl which is optionally partially or fully halogenated,halogen, nitrile, C₁₋₃ alkoxy which is optionally partially or fullyhalogenated, phenyloxy, naphthyloxy, heterocyclyloxy wherein theheterocyclyl moiety is selected from the group hereinabove described,nitro, amino, mono- or di-(C₁₋₃)alkylamino, phenylamino, naphthylamino,heterocyclylamino wherein the heterocyclyl moiety is selected from thegroup hereinabove described, NH₂C(O), a mono- or di-(C₁₋₃)alkylaminocarbonyl, C₁₋₄ alkyl-OC(O), C₁₋₅ alkyl-C(O)—C₁₋₄ branched orunbranched alkyl, an amino-C₁₋₅ alkyl, mono- or di-(C₁₋₃)alkylamino-C₁₋₅alkyl, R₉—C₁₋₅ alkyl, R₁₀—C₁₋₅ alkoxy, R₁₁—C(O)—C₁₋₅ alkyl and R₁₂—C₁₋₅alkyl(R₁₃)N;

c) cycloalkyl selected from the group consisting of cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclopentyl,bicyclohexyl and bicycloheptyl, wherein the cycloalkyl is optionallypartially or fully halogenated and optionally substituted with one tothree C₁₋₃ alkyl groups;

d) C₅₋₇ cycloalkenyl selected from the group consisting ofcyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl,cycloheptadienyl, bicyclohexenyl and bicycloheptenyl, wherein suchcycloalkenyl group is optionally substituted with one to three C₁₋₃alkyl groups;

e) acetyl, aroyl, C₁₋₆alkoxycarbonylC₁₋₆ alkyl or phenylsulfonyl; or

f) C₁₋₆ branched or unbranched alkyl optionally partially or fullyhalogenated; or R₁ and R₂ taken together optionally form a fused phenylor pyridinyl ring;

each R₈ and R₁₃ is independently selected from the group consisting of:hydrogen and C₁₋₄ branched or unbranched alkyl optionally partially orfully halogenated;

each R₄, R₅, R₆, R₇, R₉, R_(10,) R₁₁ and R₁₂ is independently selectedfrom the group consisting of morpholine, piperidine, piperazine,imidazole and tetrazole;

m is 0, 1 or 2;

W is O or S;

wherein X is directly attached to one or two —Y—Z, and pharmaceuticallyacceptable derivatives thereof.

In one embodiment of the invention there are compounds of theformula(Ia) as provided above and wherein:

Ar₂ is naphthyl, tetrahydronaphthyl, indanyl or indenyl and W is O.

In another embodiment of the invention are compounds of the formula (Ia)as provided immediately above and wherein:

Ar₁ is thiophene or pyrazole each substituted independently by one tothree R₁, R₂ or R₃;

X is:

a C₅₋₇ cycloalkyl or cycloalkenyl optionally substituted with one to twooxo groups or one to three C₁₋₄ alkyl, C₁₋₄ alkoxy or C₁₋₄ alkylaminochains each being branched or unbranched;

phenyl, indanyl, furanyl, thienyl, imidazolyl, pyridinyl, pyrazinyl,tetrahydrapyridinyl, pyrimidinyl, pyridinonyl, piperdinyl, benzimidazoleor piperazinyl; each being optionally independently substituted with oneto three C₁₋₄ alkyl, C₁₋₄alkoxy, hydroxy, nitrile, amino, mono- ordi-(C₁₋₃ alkyl)amino, mono- or di-(C₁₋₃ alkylamino)carbonyl, NH₂C(O),C₁₋₆ alkyl-S(O)_(m) or halogen;

Y is:

a bond or a C₁₋₄ saturated or unsaturated branched or unbranched carbonchain optionally partially or fully halogenated, wherein one or more Catoms are optionally replaced by O or N, and wherein Y is optionallyindependently substituted with one to two oxo groups, nitrile, phenyl,hydroxy or one or more C₁₋₄ alkyl optionally substituted by one or morehalogen atoms;

Z is:

phenyl, heteroaryl selected from pyridinyl, imidazolyl, furanyl andthienyl, heterocycle selected from piperazinyl, 2-oxa-5-aza-bicyclo[2.2.l]heptanyl, pentamethylene sulfidyl, pentamethylene sulfoxidyl,pentamethylene sulfonyl, tetrahydrofuranyl, morpholino, thiomorpholinoand piperidinyl,

each of the aforementioned Z are optionally substituted with one tothree halogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₃ alkoxy-C₁₋₃ alkyl, C₁₋₆alkoxycarbonyl, aroyl, morpholinocarbonyl, C₁₋₃acyl, oxo, hydroxy,pyridinyl-C₁₋₃ alkyl, imidazolyl-C₁₋₃ alkyl, tetrahydrofuranyl-C₁₋₃alkyl, nitrile-C₁₋₃ alkyl, nitrile, carboxy, phenyl wherein the phenylring is optionally substituted with one to two halogen, C₁₋₆ alkoxy,hydroxy or mono- or di-(C₁₋₃ alkyl)amino, amino-S(O)_(m), C₁₋₆alkyl-S(O)_(m), or phenyl-S(O)_(m) wherein the phenyl ring is optionallysubstituted with one to two halogen, C₁₋₆ alkoxy, hydroxy, halogen ormono- or di-(C₁₋₃ alkyl)amino;

or Z is optionally substituted with one to three amino, aminocarbonyl oramino-C₁₋₃ alkyl wherein the N atom is optionally independently mono- ordi-substituted by aminoC₁₋₆ alkyl, C₁₋₃ alkyl, arylC₀₋₃ alkyl, C₁₋₅alkoxyC₁₋₃ alkyl, C₁₋₅ alkoxy, aroyl, C₁₋₃acyl, C₁₋₃ alkyl-S(O)_(m)- orarylC₀₋₃ alkyl-S(O)_(m)-, each of the aforementioned alkyl and arylattached to the amino group are optionally substituted with one to twohalogen, C₁₋₆ alkyl or C₁₋₆ alkoxy;

or Z is optionally substituted with one to three aryl, heterocycle orheteroaryl as hereinabove described in this paragraph each in turn isoptionally substituted by halogen, C₁₋₆ alkyl or C₁₋₆ alkoxy;

or Z is hydroxy, hydroxyC₁₋₃ alkyl, halogen, nitrile, amino wherein theN atom is optionally independently mono- or di-substituted by aroyl,C₁₋₃acyl, C₁₋₆ alkyl, C₁₋₅ alkoxyC₁₋₃ alkyl, pyridinylC₁₋₃ alkyl,tetrahydrafuranylC₁₋₃ alkyl, nitrileC₁₋₄ alkyl or phenyl wherein thephenyl ring is optionally substituted with one to two halogen, C₁₋₆alkoxy, hydroxy or mono- or di-(C₁₋₃ alkyl)amino,

or Z is C₁₋₆ alkyl branched or unbranched, C₁₋₆alkoxy or nitrileC₁₋₄alkyl;

R₁ is:

C₁₋₄ branched or unbranched alkyl optionally partially or fullyhalogenated;

cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyloptionally partially or fully halogenated and optionally substitutedwith one to three C₁₋₃ alkyl groups, or an analog of such cycloalkylgroup wherein one to three ring methylene groups are replaced by groupsindependently selected from the group consisting of O, S and NH;

C₃₋₁₀ branched alkenyl optionally partially or fully halogenated andoptionally substituted with one to three C₁₋₅ branched or unbranchedalkyl;

cyclopentenyl and cyclohexenyl optionally substituted with one to threeC₁₋₃ alkyl groups;

R₂ is:

C₁₋₆ branched or unbranched alkyl optionally partially or fullyhalogenated and optionally substituted with nitrile;

R₃ is:

phenyl or heterocyclic group selected from the group consisting ofpyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl and pyrazolyl, whereinsuch phenyl or heterocyclic group is optionally substituted with one tofive groups selected from the group consisting of a phenyl, heterocycleselected from the group hereinabove described in this paragraph, C₁₋₆branched or unbranched alkyl which is optionally partially or fullyhalogenated, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, bicyclopentyl, bicyclohexyl, bicycloheptyl, phenyl C₁₋₅alkyl, naphthyl C₁₋₅ alkyl, halogen, hydroxy, oxo, nitrile, C₁₋₃ alkoxyoptionally be partially or fully halogenated, C₁₋₃ alkoxyC₁₋₅ alkyl,C₁₋₃thioalkyl, C₁₋₃thioalkylC₁₋₅ alkyl, phenyloxy, naphthyloxy,heteraryloxy wherein the heterocyclic moiety is selected from the grouphereinabove described in this paragraph, nitro, amino, mono- ordi-(C₁₋₃)alkylamino, phenylamino, naphthylamino, heterocyclylaminowherein the heterocyclyl moiety is selected from the group hereinabovedescribed in this paragraph, NH₂C(O), a mono- or di-(C₁₋₃)alkylaminocarbonyl, C₁₋₅ alkyl-C(O)—C₁₋₄ alkyl, amino-C₁₋₅ alkyl, mono- ordi-(C₁₋₃)alkylamino-C₁₋₅ alkyl, amino-S(O)₂, di-(C₁₋₃)alkylamino-S(O)₂,R₄—C₁₅ alkyl, R₅—C₁₋₅ alkoxy, R₆—C(O)—C₁₋₅ alkyl and R₇—C₁₋₅ alkyl(R₈)N,carboxy-mono- or di-(C₁₋₅ amino;

a fused aryl selected from the group consisting of benzocyclobutanyl,indanyl, indenyl; wherein the fused aryl is substituted with 0 to 3groups independently selected from the group consisting of phenyl,naphthyl and heterocyclyl selected from the group consisting ofpyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl,pyrazolyl, thienyl, furyl, isoxazolyl, and isothiazolyl, C₁₋₆ branchedor unbranched alkyl which is optionally partially or fully halogenated,halogen, nitrile, C₁₋₃ alkoxy which is optionally partially or fullyhalogenated, phenyloxy, naphthyloxy, heterocyclyloxy wherein theheterocyclyl moiety is selected from the group hereinabove described inthis paragraph, nitro, amino, mono- or di-(C₁₋₃)alkylamino, phenylamino,naphthylamino, heterocyclylamino wherein the heterocyclyl moiety isselected from the group hereinabove described in this paragraph,NH₂C(O), a mono- or di-(C₁₋₃)alkyl aminocarbonyl, C₁₋₄ alkyl-OC(O), C₁₋₅alkyl-C(O)—C₁₋₄ branched or unbranched alkyl, an amino-C₁₋₅ alkyl, mono-or di-(C₃) alkylamino-C₁₋₅ alkyl, R₉—C₁₋₅ alkyl, R₁₀—C₁₋₅ alkoxy,R₁₁—C(O)—C₁₋₅ alkyl and R₁₂—C₁₋₅ alkyl(R₁₃)N;

cycloalkyl selected from the group consisting of cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, wherein the cycloalkylis optionally partially or fully halogenated and optionally substitutedwith one to three C₁₋₃ alkyl groups;

C₁₋₆alkoxycarbonylC₁₋₆ alkyl;

or R₁ and R₂ taken together optionally form a fused phenyl or pyridinylring;

each R₈ and R₁₃ is independently selected from the group consisting of:hydrogen and C₁₋₄ branched or unbranched alkyl optionally partially orfully halogenated; and

each R₄, R₅, R₆, R₇, R₉, R₁₀, R₁₁ and R₁₂ is independently selected fromthe group consisting of morpholine, piperidine, piperazine, imidazoleand tetrazole;

wherein X is directly attached to one —Y—Z.

In yet still another embodiment of the invention there are the compoundsof the formula(Ia) as provided immediately above and wherein:

Ar₁ is pyrazole;

X is:

cyclopentenyl, cyclohexenyl, cycloheptenyl, optionally substituted withan oxo group or one to three C₁₋₄ alkyl, C₁₋₄ alkoxy or C₁₋₄ alkylaminochains each being branched or unbranched;

phenyl, furanyl, thienyl, pyridinyl, pyrazinyl piperidinyl orpyrimidinyl each being optionally independently substituted with one tothree C₁₋₂ alkyl, C₁₋₂alkoxy, hydroxy or halogen;

Z is:

phenyl, heteroaryl selected from pyridinyl, imidazolyl and furanyl,heterocycle selected from 2-oxa-5-aza-bicyclo[2.2.1]heptanyl,pentamethylene sulfidyl, pentamethylene sulfoxidyl, pentamethylenesulfonyl, tetrahydrofuranyl, tetrahydropyranyl, piperazinyl, morpholino,thiomorpholino, thiomorpholino sulfoxide and piperidinyl, each of theaforementioned Z are optionally substituted with one to three halogen,C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₃ alkoxy-C₁₋₃ alkyl, C₁₋₆ alkoxycarbonyl,aroyl, morpholinocarbonyl, C₁₋₃acyl, oxo, hydroxy, pyridinyl-C₁₋₃ alkyl,imidazolyl-C₁₋₃ alkyl, tetrahydrofuranyl-C₁₋₃ alkyl, nitrile-C₁₋₃ alkyl,nitrile, carboxy, phenyl wherein the phenyl ring is optionallysubstituted with one to two halogen, C₁₋₆ alkoxy, hydroxy or mono- ordi-(C₁₋₃ alkyl)amino, amino-S(O)_(m), C₁₋₆ alkyl-S(O)_(m), orphenyl-S(O)_(m) wherein the phenyl ring is optionally substituted withone to two halogen, C₁₋₆ alkoxy, hydroxy, halogen or mono- or di-(C₁₋₃alkyl)amino;

or Z is optionally substituted with one to three amino, aminocarbonyl oramino-C₁₋₃ alkyl wherein the N atom is optionally independently mono- ordi-substituted by amino C₁₋₆ alkyl, C₁₋₃ alkyl, arylC₀₋₃ alkyl, C₁₋₅alkoxyC₁₋₃ alkyl, C₁₋₅ alkoxy, aroyl, C₁₋₃acyl, C₁₋₃ alkyl-S(O)_(m)-,pyridinylC₀₋₃ alkyl, tetrahydrafuranylC₀₋₃ alkyl, or arylC₀₋₃alkyl-S(O)_(m)— each of the aforementioned alkyl and aryl attached tothe amino group is optionally substituted with one to two halogen, C₁₋₆alkyl or C₁₋₆ alkoxy;

or Z is hydroxy, hydroxyC₁₋₃ alkyl, halogen, nitrile, amino wherein theN atom is optionally independently mono- or di-substituted by C₁₋₆alkyl, pyridinylC₀₋₃ alkyl, tetrahydrafuranylC₀₋₃ alkyl, C₁₋₅ alkoxyC₁₋₃alkyl, C₁₋₃ acyl, nitrileC₁₋₄ alkyl or phenyl wherein the phenyl ring isoptionally substituted with one to two halogen, C₁₋₆ alkoxy, hydroxy ormono- or di-(C₁₋₃ alkyl)amino,

or Z is C₁₋₆ alkyl branched or unbranched, C₁₋₆alkoxy or nitrileC₁₋₄alkyl;

R₁ is:

C₁₋₄ branched or unbranched alkyl optionally partially or fullyhalogenated;

cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl and cycloheptanyloptionally partially or fully halogenated and optionally substitutedwith one to three C₁₋₃ alkyl groups, or an analog of such cycloalkylgroup wherein one to three ring methylene groups are replaced by groupsindependently selected from the group consisting of O, S and NH;

C₃₋₁₀ branched alkenyl optionally partially or fully halogenated andoptionally substituted with one to three C₁₋₃ branched or unbranchedalkyl;

cyclopentenyl and cyclohexenyl optionally substituted with one to threeC₁₋₃ alkyl groups;

R₂ is:

a C₁₋₆ branched or unbranched alkyl optionally partially or fullyhalogenated and optionally substituted with nitrile;

R₃ is:

phenyl or heterocyclic group selected from the group consisting ofpyridinyl, pyrimidinyl, pyridazinyl and pyrazolyl, wherein such phenylor heterocyclic group is optionally substituted with one to five groupsselected from the group consisting of a phenyl, heterocycle selectedfrom the group hereinabove described in this paragraph, C₁₋₆ branched orunbranched alkyl which is optionally partially or fully halogenated,phenyl C₁₋₅ alkyl, halogen, hydroxy, oxo, nitrile, C₁₋₃ alkoxyoptionally partially or fully halogenated, C₁₋₃thioalkyl,C₁₋₃thioalkylC₁₋₅ alkyl, amino, mono- or di-(C₁₋₃)alkylamino, NH₂C(O) ora mono- or di-(C₁₋₃)alkyl aminocarbonyl,

C₁₋₆alkoxycarbonylC₁₋₆ alkyl;

or R₃ is cyclopropyl or cyclopentyl each optionally partially or fullyhalogenated and optionally substituted with one to three C₁₋₃ alkylgroups

or R₁ and R₂ taken together optionally form a fused phenyl or pyridinylring.

In yet a further embodiment of the invention there are the compounds ofthe formula(Ia) as provided immediately above and wherein:

Y is —CH₂—, —O—(CH₂)₀₋₃—, —CH₂CH₂—, —CH₂NH—, —CH₂CH₂—NH—, NH—CH₂CH₂—,—CH₂—NH—CH₂—, —NH—, —NH—C(O)—, —C(O)—, —CH(OH)—, —CH₂(CH₂CH₃)—or a bond;

X is:

cyclohexenyl optionally substituted with an oxo group or one to threeC₁₋₄ alkyl, C₁₋₄ alkoxy or C₁₋₄ alkylamino chains each being branched orunbranched;

phenyl, pyridinyl, pyrazinyl, piperidinyl or pyrimidinyl each beingoptionally independently substituted with one to three C₁₋₂ alkyl,C₁₋₂alkoxy, hydroxy or halogen;

Z is:

phenyl, heteroaryl selected from pyridinyl, imidazolyl and furanyl,heterocycle selected from 2-oxa-5-aza-bicyclo[2.2.1]heptanyl,pentamethylene sulfidyl, pentamethylene sulfoxidyl, pentamethylenesulfonyl, tetrahydrofuranyl, tetrahydropyranyl, piperazinyl, morpholino,thiomorpholino, thiomorpholino sulfoxide and piperidinyl, each of theaforementioned Z are optionally substituted with one to three halogen,C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₃ alkoxy-C₁₋₃ alkyl, C₁₋₆ alkoxycarbonyl,aroyl, morpholinocarbonyl, C₁₋₃ acyl, oxo, hydroxy, pyridinyl-C₁₋₃alkyl, imidazolyl-C₁₋₃ alkyl, tetrahydrofuranyl-C₁₋₃ alkyl, nitrile-C₁₋₃alkyl, nitrile, carboxy, phenyl wherein the phenyl ring is optionallysubstituted with one to two halogen, C₁₋₆ alkoxy, hydroxy or mono- ordi-(C₁₋₃ alkyl)amino, amino-S(O)_(m), C₁₋₆ alkyl-S(O)_(m), orphenyl-S(O)_(m) wherein the phenyl ring is optionally substituted withone to two halogen, C₁₋₆ alkoxy, hydroxy, halogen or mono- or di-(C₁₋₃alkyl)amino;

or Z is optionally substituted with one to three amino or aminocarbonylwherein the N atom is optionally independently mono- or di-substitutedby aminoC₁₋₆ alkyl, C₁₋₃ alkyl, arylC₀₋₃ alkyl, C₁₋₅ alkoxyC₁₋₃ alkyl,C₁₋₅ alkoxy, aroyl, C₁₋₃acyl, C₁₋₃ alkyl-S(O)_(m)— or arylC₀₋₃alkyl-S(O)_(m)— each of the aforementioned alkyl and aryl attached tothe amino group is optionally substituted with one to two halogen, C₁₋₆alkyl or C₁₋₆ alkoxy;

or Z is hydroxy, hydroxyC₁₋₃ alkyl, halogen, nitrile, amino wherein theN atom is optionally independently mono- or di-substituted by C₁₋₃alkyl, pyridinylC₁₋₂ alkyl, tetrahydrafuranylC₁₋₂ alkyl, C₁₋₃ alkoxyC₁₋₃alkyl, C₁₋₃acyl, nitrileC₁₋₄ alkyl, phenyl wherein the phenyl ring isoptionally substituted with one to two halogen, C₁₋₆ alkoxy, hydroxy ormono- or di-(C₁₋₃ alkyl)amino,

or Z is C₁₋₆ alkyl branched or unbranched, C₁₋₆alkoxy or nitrileC₁₋₄alkyl;

R₁ is:

C₁₋₄ branched or unbranched alkyl optionally partially or fullyhalogenated;

R₂ is:

a C₁₋₃ branched or unbranched alkyl optionally partially or fullyhalogenated and optionally substituted with nitrile;

R₃ is:

phenyl or heterocyclic group selected from the group consisting ofpyridinyl, pyrimidinyl, and pyrazolyl, wherein such phenyl orheterocyclic group is optionally substituted with one to five groupsselected from the group consisting of C₁₋₃ branched or unbranched alkylwhich is optionally partially or fully halogenated, C₁₋₃ alkoxy whichoptionally partially or fully halogenated, C₁₋₃ thioalkyl, C₁₋₃thioalkylC₁₋₅ alkyl, amino or NH₂C(O);

C₁₋₃alkoxycarbonyl;

or R₃ is cyclopropyl or cyclopentyl each optionally partially or fullyhalogenated and optionally substituted with one to three C₁₋₃ alkylgroups.

In a yet still further embodiment of the invention there are thecompounds of the formula(Ia) as provided immediately above and wherein:

Ar₁ is 5-tert-butyl-pyrazol-3-yl; wherein the pyrazole ring issubstituted independently by one to two R₂ or R₃;

X is:

cyclohexenyl;

phenyl, pyridinyl, pyrazinyl, piperidinyl or pyrimidinyl each beingoptionally independently substituted with C₁₋₂alkoxy or hydroxy;

Z is:

phenyl, heteroaryl selected from pyridinyl and furanyl, heterocycleselected from 2-oxa-5-aza-bicyclo[2.2.1]heptanyl, pentamethylenesulfidyl, pentamethylene sulfoxidyl, tetrahydrofuranyl, piperazinyl,morpholino, thiomorpholino and piperidinyl, each of the aforementioned Zare optionally substituted with one to three C₁₋₃ alkyl, C₁₋₃ alkoxy,oxo, hydroxy or NH₂C(O)—;

or Z is hydroxyC₁₋₃ alkyl, amino wherein the N atom is optionallyindependently mono- or di-substituted by pyridinylmethyl,tetrahydrafiranylmethyl, C₁₋₃ alkoxyC₁₋₃ alkyl, C₁₋₃acyl or nitrileC₁₋₄alkyl,

or Z is nitrileC₁₋₄ alkyl;

R₃ is:

phenyl or heterocyclic group selected from the group consisting ofpyridinyl, pyrimidinyl, and pyrazolyl, wherein such phenyl orheterocyclic group is optionally substituted with one to two groupsselected from the group consisting of C₁₋₂ alkyl which is optionallypartially or fully halogenated, C₁₋₂ alkoxy which optionally partiallyor fully halogenated, C₁₋₂thioalkyl, C₁₋₂thioalkylC₁₋₃ alkyl, amino orNH₂C(O);

C₁₋₃alkoxycarbonyl;

or R₃ is cyclopropyl or cyclopentyl each optionally partially or fullyhalogenated and optionally substituted with one to three C₁₋₃ alkylgroups.

In an even further embodiment of the invention there are the compoundsof the formula(Ia) as provided immediately above and wherein X ispyridinyl.

In a yet still even further embodiment of the invention there arecompounds of the formula(Ia) as provided immediately above and whereinthe pyridinyl is attached to Ar₁ via the 3-pyridinyl position.

The following are representative compounds of formula(Ia) of theinvention:

1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(4-morpholin-4-yl-methylphenyl)-naphthalen-1-yl]-urea;

1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[3-(4-morpholin-4-yl-methylphenyl)-naphthalen-1-yl]-urea;

1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(5-morpholin-4-yl-methylfuran-2-yl-naphthalen-1-yl]-urea;

1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(3-(morpholin-4-yl-methyl)cyclohexenyl)-naphthalen-1-yl]-urea;

1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-(4-morpholin-4-yl)ethylphenyl)-naphthalen-1-yl]-urea;

1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(4-dimethylaminomethylphenyl)-naphthalen-1-yl]-urea;

1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(5-(morpholin-4-yl-methyl)pyridin-2-yl)-naphthalen-1-yl]-urea;

1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(6-(morpholin-4-yl-methyl)pyridin-3-yl)-naphthalen-1-yl]-urea;

1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-(morpholin-4-yl-methyl)pyridin-3-yl)-naphthalen-1-yl]-urea;

1-[5-tert-butyl-2-methyl-2H-pyrazol-3-yl]-3-[4-(6-(morpholin-4-yl-methyl)pyridin-3-yl)-naphthalen-1-yl]-urea;

1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(3-(2-(morpholin-4-yl)ethylamino)cyclohexenyl)-naphthalen-1-yl]-urea;

1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(3,4-(morpholin-4-yl-methyl)phenyl)-naphthalen-1-yl]-urea;

1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(4-methylpiperzin-1-yl-methyl)phenyl)-naphthalen-1-yl]-urea;

1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(piperdin-1-yl-methyl)phenyl)-naphthalen-1-yl]-urea;

1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(3-(2-(phenyl-2-yl)ethylamino)cyclohexenyl)-naphthalen-1-yl]-urea;

1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(4-(2-(pyridin-4-yl)ethylaminomethyl)phenyl)naphthalen-1-yl]-urea;

1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(4-(pyridin-3-yl-methylaminomethyl)phenyl)naphthalen-1-yl]-urea;

1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(4-(3,4-dimethoxyphenylmethyl)-3-hydroxyphenyl)naphthalen-1-yl]-urea;

1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(6-oxo-1,6-dihydro-pyridin-3-yl)naphthalen-1-yl]-urea;

1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(4-(morpholin-4-yl-methyl)phenyl)naphthalen-1-yl]-urea;

1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(4-(morpholin-4-yl-methyl)imidazol-1-yl)naphthalen-1-yl]-urea;

1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(4-(morpholin-4-yl-methyl)imidazol-1-yl)naphthalen-1-yl]-urea;

1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(4-(furan-3-yl-methyl)-3-hydroxyphenyl)naphthalen-1-yl]-urea;

1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-(4-hydroxybutylamino)pyridin-3-yl)-naphthalen-1-yl]-urea;

1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(4-(pyridin-3-yl-methyl)-3-hydroxyphenyl)naphthalen-1-yl]-urea;

1-[5-tert-butyl-2-(4-methyl-3-carbamylphenyl)-2H-pyrazol-3-yl]-3-[4-(6-(morpholin-4-yl-methyl)pyridin-3-yl)naphthalen-1-yl]-urea;

1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(4-(imidazol-2-yl-methyl)-3-hydroxyphenyl)naphthalen-1-yl]-urea;

1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(4-(N-3-hydroxymorpholin-4-yl-methyl)phenyl)naphthalen-1-yl]-urea;

1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(4-(N-2-methyoxyethy-N-methylaminomethyl)phenyl)naphthalen-1-yl]-urea;

1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(4-(4-hydroxymorpholin-4-yl-methyl)phenyl)naphthalen-1-yl]-urea;

1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(3-(morpholin-4-yl-methyl)cyclohexenyl)-naphthalen-1-yl]-urea;

1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(4-(tetrahydrofuran-3-methyl)-3-hydroxyphenyl)naphthalen-1-yl]-urea;

1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(4-(N,N-di-(2-methoxyethyl)aminomethyl)phenyl)naphthalen-1-yl]-urea;

1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-(3-cyanopropoxy)pyridin-3-yl)naphthalen-1-yl]-urea;

1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(4-morpholin-4-yl-methyl-piperdinyl)naphthalen-1-yl]-urea;

1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(4-(N,N-di-(2-cyanoethyl)aminomethyl)phenyl)naphthalen-1-yl]-urea;

1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(1-morpholin-4-yl-indan-5-yl-naphthalen-1-yl]-urea;

1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(4-(furan-2-yl-methyl)-3-hydroxyphenyl)naphthalen-1-yl]-urea;

1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(4-(thiomorpholin-4-methyl)phenyl)naphthalen-1-yl]-urea;

1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(4-(3-carboxamidomorpholin-4-yl-methyl)phenyl)naphthalen-1-yl]-urea;

1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(4-(2-methyl-3-oxo-piperzin-1-yl-methyl)phenyl)naphthalen-1-yl]-urea;

1-[5-tert-butyl-2-(2-methylpyrimidin-5-yl)-2H-pyrazol-3-yl]-3-[4-(6-(morpholin-4-yl-methyl)pyridin-3-yl)naphthalen-1-yl]-urea;

1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-(4-hydroxybutyloxy)pyridin-3-yl)-naphthalen-1-yl]-urea;

1-[3-tert-butyl-1′H-[1,4′]bipyrazol-5-yl]-3-[4-(6-(morpholin-4-yl-methyl)pyridin-3-yl)naphthalen-1-yl]-urea;

1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(4-(furan-2-yl-methyl)-3-methoxyphenyl)naphthalen-1-yl]-urea;

1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(5-(morpholin-4carbonyl)pyrazin-2-yl)naphthalen-1-yl]-urea;

1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-(tetrahydrothiopyran-4-yl-amino)pyridin-3-yl)-naphthalen-1-yl]-urea;

1-[5-tert-butyl-2-(2-cyanoethyl)-2H-pyrazol-3-yl]-3-[4-(6-(morpholin-4-yl-methyl)pyridin-3-yl)-naphthalen-1-yl]-urea;

1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-(2,6-dimethylmorpholin-4-yl-methyl)pyridin-3-yl)-naphthalen-1-yl]-urea;

1-[5-tert-butyl-2-(2-methoxypyridin-5-yl)-2H-pyrazol-3-yl]-3-[4-(6-(morpholin-4-yl-methyl)pyridin-3-yl)-naphthalen-1-yl]-urea;

1-[5-tert-butyl-2-(2-aminoypyridin-5-yl)-2H-pyrazol-3-yl]-3-[4-(6-(morpholin-4-yl-methyl)pyridin-3-yl)-naphthalen-1-yl]-urea;

1-[5-tert-butyl-2-(6-oxo-1,6-dihydropyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-(morpholin-4-yl-methyl)pyridin-3-yl)-naphthalen-1-yl]-urea;

1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-(morpholin-4-yl-4-carbonyl)pyridin-3-yl)-naphthalen-1-yl]-urea;

1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-(2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl-methyl)pyridin-3-yl)-naphthalen-1-yl]-urea;

1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(4-(3-carbamylphenyl)naphthalen-1-yl]-urea;

1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(4-(N-(2-cyanoethyl)-N-(pyridin-3-yl-methyl)aminomethyl)phenyl)-naphthalen-1-yl]-urea;

1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(4-(N-(2-cyanoethyl)-N-(pyridin-2-yl-methyl)aminomethyl)phenyl)-naphthalen-1-yl]-urea;

1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(4-(N-(2-cyanoethyl)-N-(tetrahydrofuran-2-yl-methyl)aminomethyl)phenyl)-naphthalen-1-yl]-urea;

1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-(morpholin-4-yl-methyl)-4-methoxypyridin-3-yl)-naphthalen-1-yl]-urea;

1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-(1-morpholin-4-yl-propyl)pyridin-3-yl)-naphthalen-1-yl]-urea;

1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-(N-(3-methoxypropyl)amino)pyridin-3-yl)-naphthalen-1-yl]-urea;

1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-(N-(3-methoxypropyl)-N-methylamino)pyridin-3-yl)-naphthalen-1-yl]-urea;

1-[3-tert-butyl-1′-methyl-1′H-[1,4′]bipyrazol-5-yl]-3-[4-(6-(morpholin-4-yl-methyl)pyridin-3-yl)naphthalen-1-yl]-urea;

1-[5-tert-butyl-2-benzyl-2H-pyrazol-3-yl]-3-[4-(6-(morpholin-4-yl-methyl)pyridin-3-yl)-naphthalen-1-yl]-urea;

1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(4-(N-N-di-(2-cyanoethyl)aminomethyl)phenyl)-naphthalen-1-yl]-urea;

1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(4-(4-carbamylphenyl)naphthalen-1-yl]-urea;

1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-(1-oxo-tetrahydrothiopyran-4-yl-amino)pyridin-3-yl)-naphthalen-1-yl]-urea;

1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-(tetrahydropyran-4yl-amino)pyridin-3-yl)-naphthalen-1-yl]-urea;

1-[3-tert-butyl-1′-(3-cyanopropyl)-1′H-[1,4′]bipyrazol-5-yl]-3-[4-(6-(morpholin-4-yl-methyl)pyridin-3-yl)naphthalen-1-yl]-urea;

1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-y]-3-[4-(3-methanesulfinylphenyl)naphthalen-1-yl]-urea;

1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(3-methanesulfonylphenyl)naphthalen-1-yl]-urea;

1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(3-sulfonamidophenyl)naphthalen-1-yl]-urea;

1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(3-(morpholin-4-yl)carbonylphenyl)naphthalen-1-yl]-urea;

1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-y]-3-[4-(5-(tetrahydrothiopyran-4yl-amino)pyrazin-2-yl)-naphthalen-1-yl]-urea;

1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-(methylcarbonylamino)pyridin-3-yl)-naphthalen-1-yl]-urea;

1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(6-(morpholin-4-yl-4-carbonyl)phenyl)-naphthalen-1-yl]-urea;

1-[3-tert-butyl-1′-(3-methylsulfanylpropyl)-1′H-[1,4′]bipyrazol-5-yl]-3-[4-(6-(morpholin-4-yl-methyl)pyridin-3-yl)naphthalen-1-yl]-urea;

1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(5-(morpholin-4-yl-carbonyl)pyridrin-3-yl)-naphthalen-1-yl]-urea;

1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(5-(morpholin-4-yl-methyl)pyrazin-2-yl)-naphthalen-1-yl]-urea;

1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-aminopyridin-3-yl)naphthalen-1-yl]-urea;

1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-(1-methylpiperdin-4-yl-amino)pyridin-3-yl)naphthalen-1-yl]-urea;

1-[5-tert-butyl-2-(2-methylpyrimidin-5-yl)-2H-pyrazol-3-yl]-3-[4-(6-(2-methyl-3-oxo-piperzin-1-yl-methyl)pyridin-3-yl)naphthalen-1-yl]-urea;

1-[5-tert-butyl-2-(2-methylpyrimidin-5-yl)-2H-pyrazol-3-yl]-3-[4-(6-(morpholin-4-yl-carbonyl)pyridin-3-yl)naphthalen-1-yl]-urea;

1-[5-tert-butyl-2-(2-methylpyrimidin-5-yl)-2H-pyrazol-3-yl]-3-[4-(6-(N,N-di-(2-methoxyethyl)aminomethyl)pyridin-3-yl)naphthalen-1-yl]-urea;

1-[5-tert-butyl-2-(2-methylpyrimidin-5-yl)-2H-pyrazol-3-yl]-3-[4-(6-(1-oxo-thiomorpholin-4-yl-methyl)pyridin-3-yl)naphthalen-1-yl]-urea;

1-[5-tert-butyl-2-(2-methylpyrimidin-5-yl)-2H-pyrazol-3-yl]-3-[4-(6-(tetrahydropyran-4-yl-amino)pyridin-3-yl)naphthalen-1-yl]-urea;

1-[5-tert-butyl-2-(2-methylpyrimidin-5-yl)-2H-pyrazol-3-yl]-3-[4-(5-(morpholin-4-yl-methyl)pyrazin-2-yl)naphthalen-1-yl]-urea;

1-[5-tert-butyl-2-(2-methylthiopyrimidin-5-yl)-2H-pyrazol-3-yl]-3-[4-(6-(morpholin-4-yl-methyl)pyridin-3-yl)naphthalen-1-yl]-urea;

1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(6-(2-methyl-3-oxo-piperzin-1-yl-methyl)pyridin-3-yl)naphthalen-1-yl]-urea;

1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(6-(pyridin-3-yl-oxy)pyridin-3-yl)naphthalen-1-yl]-urea

1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(6-(pyridin-3-yl-amino)pyridin-3-yl)naphthalen-1-yl]-urea;

1-[5-tert-butyl-2-(2-methoxypyrimidin-5-yl)-2H-pyrazol-3-yl]-3-[4-(6-(morpholin-4-yl-methyl)pyridin-3-yl)naphthalen-1-yl]-urea;

1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(5-carbamylpyridin-3-yl)naphthalen-1-yl]-urea;

1-[5-tert-butyl-2-(2-aminopyrimidin-5-yl)-2H-pyrazol-3-yl]-3-[4-(6-(morpholin-4-yl-methyl)pyridin-3-yl)naphthalen-1-yl]-urea;

1-[5-tert-butyl-2-(2-methylpyrimidin-5-yl)-2H-pyrazol-3-yl]-3-[4-(4-(morpholin-4-yl-methyl)phenyl)naphthalen-1-yl]-urea;

1-[3-tert-butyl-1′-methyl-1′H-[1,4′]bipyrazol-5-yl]-3-[4-(6-(morpholin-4-methyl)phenyl)naphthalen-1-yl]-urea;

1-[5-tert-butyl-2-(2-cyclopropylpyrimidin-5-yl)-2H-pyrazol-3-yl]-3-[4-(6-(morpholin-4-yl-methyl)pyridin-3-yl)naphthalen-1-yl]-urea;

1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-(pyridin-3-yl-amino)pyrimidin-5-yl)naphthalen-1-yl]-urea;

1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(6-(1-oxo-tetrahydrothiopyran-4-yl-amino)pyridin-3-yl)naphthalen-1-yl]-urea;

1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(6-(thiomorpholin-4-yl-methyl)pyridin-6-yl)naphthalen-1-yl]-urea;

1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(3-benzyl-3H-imidazo[4,5-b]pyridin-3-yl)naphthalen-1-yl]-urea;

1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-(pyridin-3-yl-methyl)pyridin-3-yl)naphthalen-1-yl]-urea;

1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-(morpholin-4-yl-carbonyl)pyrimidin-5-yl)naphthalen-1-yl]-urea;

1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-(morpholin-4-yl-methyl)pyrimidin-5-yl)naphthalen-1-yl]-urea;

1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(3-amino-4-carbamylphenyl)naphthalen-1-yl]-urea;

1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(6-(1-oxo-thiomorpholin-4-yl-methyl)pyridin-3-yl)naphthalen-1-yl]-urea;

1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(6-(pyridin-3-yl-methyl)pyridin-3-yl)naphthalen-1-yl]-urea;

1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(6-(hydroxy-pyridin-3-yl-methyl)pyridin-3-yl)naphthalen-1-yl]-urea;

1-[5-tert-butyl-2-(2-methylpyrimidin-5-yl)-2H-pyrazol-3-yl]-3-[4-(2-(morpholin-4-methyl)pyrimidin-5-yl)naphthalen-1-yl]-urea;

and the pharmaceutically acceptable derivatives thereof.

In another embodiment of the invention there are provided the followingcompounds of the formula(Ia):

1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(5-(morpholin-4-yl-methyl)pyridin-2-yl)-naphthalen-1-yl]-urea;

1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(6-(morpholin-4-yl-methyl)pyridin-3-yl)-naphthalen-1-yl]-urea;

1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(3-(2-(pyridin-2-yl)ethylamino)cyclohexenyl)-naphthalen-1-yl]-urea;

1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(4-(pyridin-3-yl-methylaminomethyl)phenyl)naphthalen-1-yl]-urea;

1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(4-(morpholin-4-yl-methyl)phenyl)naphthalen-1-yl]-urea;

1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-(4-hydroxybutylamino)pyridin-3-yl)-naphthalen-1-yl]-urea;

1-[5-tert-butyl-2-(4-methyl-3-carbamylphenyl)-2H-pyrazol-3-yl]-3-[4-(6-(morpholin-4-yl-methyl)pyridin-3-yl)naphthalen-1-yl]-urea;

1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(4-(3-hydroxymorpholin-1-yl-methyl)phenyl)naphthalen-1-yl]-urea;

1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(4-(4-hydroxymorpholin-4-yl-methyl)phenyl)naphthalen-1-yl]-urea;

1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(3-(morpholin-4-yl-methyl)cyclohexenyl)-naphthalen-1-yl]-urea;

1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(4-(tetrahydrofuran-3-yl-methyl)-3-hydroxyphenyl)naphthalen-1-yl]-urea;

1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(4-(N,N-di-(2-methoxyethylaminomethyl)phenyl)naphthalen-1-yl]-urea;

1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-(3-cyanopropoxy)pyridin-3-yl)naphthalen-1-yl]-urea;

1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(4-morpholin-4-yl-methyl-piperdinyl)naphthalen-1-yl]-urea;

1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(4-(N,N-di-(2-cyanoethyl)aminomethyl)phenyl)naphthalen-1-yl]-urea;

1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(4-(furan-2-yl-methyl)-3-hydroxyphenyl)naphthalen-1-yl]-urea;

1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(4-(thiomorpholin-4-yl-methyl)phenyl)naphthalen-1-yl]-urea;

1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(4-(3-carboxamidopiperidin-1-yl-methyl)phenyl)naphthalen-1-yl]-urea;

1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(4-(2-methyl-3-oxo-piperzin-1-yl-methyl)phenyl)naphthalen-1-yl]-urea;

1-[5-tert-butyl-2-(2-methylpyrimidin-5-yl)-2H-pyrazol-3-yl]-3-[4-(6-(morpholin-4-methyl)pyridin-3-yl)naphthalen-1-yl]-urea;

1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-(4-hydroxybutyloxy)pyridin-3-yl)-naphthalen-1-yl]-urea;

1-[3-tert-butyl-1′H-[1,4′]bipyrazol-5-yl]-3-[4-(6-(morpholin-4-yl-methyl)pyridin-3-yl)naphthalen-1-yl]-urea;

1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-(tetrahydrothiopyran-4-yl-amino)pyridin-3-yl)-naphthalen-1-yl]-urea;

1-[5-tert-butyl-2-(2-cyanoethyl)-2H-pyrazol-3-yl]-3-[4-(6-(morpholin-4-yl-methyl)pyridin-3-yl)-naphthalen-1-yl]-urea;

1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-(2,6-dimethylmorpholin-4-yl-methyl)pyridin-3-yl)-naphthalen-1-yl]-urea;

1-[5-tert-butyl-2-(2-methoxypyridin-5-yl)-2H-pyrazol-3-yl]-3-[4-(6-(morpholin-4-yl-methyl)pyridin-3-yl)-naphthalen-1-yl]-urea;

1-[5-tert-butyl-2-(2-aminoypyridin-5-yl)-2H-pyrazol-3-yl]-3-[4-(6-(morpholin-4-yl-methyl)pyridin-3-yl)-naphthalen-1-yl]-urea;

1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-(morpholin-4-yl-4-carbonyl)pyridin-3-yl)-naphthalen-1-yl]-urea;

1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-(2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl-methyl)pyridin-3-yl)-naphthalen-1-yl]-urea;

1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(4(N-(2-cyanoethyl)-N-(pyridin-3-yl-methyl)aminomethyl)phenyl)-naphthalen-1-yl]-urea;

1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(4-(N-(2-cyanoethyl)-N-(tetrahydrofuran-2-yl-methyl)aminomethyl)phenyl)-naphthalen-1-yl]-urea;

1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-(morpholin-4-yl-methyl)-4-methoxypyridin-3-yl)-naphthalen-1-yl]-urea;

1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-(1-morpholin-4-yl-propyl)pyridin-3-yl)-naphthalen-1-yl]-urea;

1-[3-tert-butyl-1′-methyl-1′H-[1,4′]bipyrazol-5-yl]-3-[4-(6-(morpholin-4-yl-methyl)pyridin-3-yl)naphthalen-1-yl]-urea;

1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-(1-oxo-tetrahydrothiopyran-4yl-amino)pyridin-3-yl)-naphthalen-1-yl]-urea;

1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-(tetrahydropyran-4yl-amino)pyridin-3-yl)-naphthalen-1-yl]-urea;

1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(5-(tetrahydrothiopyran-4yl-amino)pyrazin-2-yl)-naphthalen-1-yl]-urea;

1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-(methylcarbonylamino)pyridin-3-yl)-naphthalen-1-yl]-urea;

1-[3-tert-butyl-1 ′-(3-methylsulfanylpropyl)-1′H-[1,4′]bipyrazol-5-yl]-3-[4-(6-(morpholin-4-yl-methyl)pyridin-3-yl)naphthalen-1-yl]-urea;

1-[5-tert-butyl-2-(2-methylpyrimidin-5-yl)-2H-pyrazol-3-yl]-3-[4-(6-(1-oxo-thiomorpholin-4-yl-methyl)pyridin-3-yl)naphthalen-1-yl]-urea;

1-[5-tert-butyl-2-(2-methylpyrimidin-5-yl)-2H-pyrazol-3-yl]-3-[4-(6-(tetrahydropyran-4-yl-amino)pyridin-3-yl)naphthalen-1-yl]-urea;

1-[5-tert-butyl-2-(2-methylthiopyrimidin-5-yl)-2H-pyrazol-3-yl]-3-[4-(6-(morpholin-4-yl-methyl)pyridin-3-yl)naphthalen-1-yl]-urea;

1-[5-tert-butyl-2-(2-aminopyrimidin-5-yl)-2H-pyrazol-3-yl]-3-[4-(6-(morpholin-4-yl-methyl)pyridin-3-yl)naphthalen-1-yl]-urea;

1-[3-tert-butyl-1′-methyl-1′H-[1,4′]bipyrazol-5-yl]-3-[4-(6-(morpholin-4-yl-methyl)phenyl)naphthalen-1-yl]-urea;

1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(6-(1-oxo-tetrahydrothiopyran-4-yl-amino)pyridin-3-yl)naphthalen-1-yl]-urea;

1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(6-(thiomorpholin-4-yl-methyl)pyridin-3-yl)naphthalen-1-yl]-urea;

1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-(morpholin-4-yl-carbonyl)pyrimidin-5-yl)naphthalen-1-yl]-urea;

1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-(morpholin-4-yl-methyl)pyrimidin-5-yl)naphthalen-1-yl]-urea;

1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(6-(1-oxo-thiomorpholin-4-yl-methyl)pyridin-3-yl)naphthalen-1-yl]-urea;

1-[5-tert-butyl-2-(2-methylpyrimidin-5-yl)-2H-pyrazol-3-yl]-3-[4-(2-(morpholin-4-yl-methyl)pyrimidin-5-yl)naphthalen-1-yl]-ureaand

the pharmaceutically acceptable derivatives thereof.

In yet another generic aspect of the invention, there are providedcompounds of the formula (II):

wherein:

G is:

an aromatic C₆₋₁₀ carbocycle or a nonaromatic C₃₋₁₀ carbocycle saturatedor unsaturated;

a 6-10 membered heteroaryl containing 1 or more heteroatoms chosen fromO, N and S;

a 5-8 membered monocyclic heterocycle containing one or more heteroatomschosen from O, N and S;

or

an 8-11 membered bicyclic heterocycle, containing one or moreheteroatoms chosen from O, N and S;

wherein G is substituted by one or more R₁, R₂ or R₃;

Ar is:

phenyl, naphthyl, quinolinyl, isoquinolinyl, tetrahydronaphthyl,tetrahydroquinolinyl, tetrahydroisoquinolinyl, benzimidazolyl,benzofuranyl, dihydrobenzofuranyl, indolinyl, benzothienyl,dihydrobenzothienyl, indanyl, indenyl or indolyl each being optionallysubstituted by one or more R₄ or R₅;

X is:

a C₅₋₈ cycloalkyl or cycloalkenyl optionally substituted with one to twooxo groups or one to three C₁₋₄ alkyl, C₁₋₄ alkoxy or C₁₋₄ alkylaminochains; phenyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl,pyridinyl, pyrimidinyl, pyridinonyl, dihydropyridinonyl, maleimidyl,dihydromaleimidyl, piperdinyl, benzimidazole, 3H-imidazo[4,5-b]pyridine,piperazinyl, pyridazinyl or pyrazinyl;

Y is:

a bond or a C₁₋₄ saturated or unsaturated branched or unbranched carbonchain optionally partially or fully halogenated, wherein one or moremethylene groups are optionally replaced by O, N, or S(O)_(m) andwherein Y is optionally independently substituted with one to two oxogroups, phenyl or one or more C₁₋₄ alkyl optionally substituted by oneor more halogen atoms;

Z is:

phenyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, imidazolyl,pyrazolyl, triazolyl, tetrazolyl, furanyl, thienyl, pyranyl each beingoptionally substituted with one to three halogen, C₁₋₆ alkyl, C₁₋₆alkoxy, hydroxy, amino, mono- or di-(C₁₋₃ alkyl)amino, C₁₋₆alkyl-S(O)_(m), CN, CONH₂, COOH or phenylamino wherein the phenyl ringis optionally substituted with one to two halogen, C₁₋₆ alkyl or C₁₋₆alkoxy;

tetrahydropyranyl, tetrahydrofuranyl, 1,3-dioxolanonyl, 1,3-dioxanonyl,1,4-dioxanyl, morpholinyl, thiomorpholinyl, thiomorpholino sulfoxidyl,thiomorpholino sulfonyl, piperidinyl, piperidinonyl, piperazinyl,tetrahydropyrimidonyl, cyclohexanonyl, cyclohexanolyl, pentamethylenesulfidyl, pentamethylene sulfoxidyl, pentamethylene sulfonyl,tetramethylene sulfide, tetramethylene sulfoxidyl or tetramethylenesulfonyl each being optionally substituted with one to three nitrile,C₁₋₆ alkyl, C₁₋₆ alkoxy, hydroxy, amino, mono- or di-(C₁₋₃alkyl)amino-C₁₋₃ alkyl, CONH₂, phenylamino-C₁₋₃ alkyl or C₁₋₃alkoxy-C₁₋₃ alkyl;

halogen, C₁₋₄ alkyl, nitrile, amino, hydroxy, C₁₋₆ alkoxy, NH₂C(O),mono- or di(C₁₋₃alkyl) aminocarbonyl, mono- or di(C₁₋₆alkyl)amino,secondary or tertiary amine wherein the amino nitrogen is covalentlybonded to C₁₋₃ alkyl or C₁₋₅ alkoxyalkyl, pyridinyl-C₁₋₃ alkyl,imidazolyl-C₁₋₃ alkyl, tetrahydrofuranyl-C₁₋₃ alkyl, nitrile-C₁₋₃ alkyl,carboxamide-C₁₋₃ alkyl, phenyl, wherein the phenyl ring is optionallysubstituted with one to two halogen, C₁₋₆ alkoxy, hydroxy or mono- ordi-(C₁₋₃ alkyl)amino, C₁₋₆ alkyl-S(O)_(m), or phenyl-S(O)_(m), whereinthe phenyl ring is optionally substituted with one to two halogen, C₁₋₆alkoxy, hydroxy, halogen or mono- or di-(C₁₋₃ alkyl)amino;

C₁₋₆ alkyl-S(O)_(m), and phenyl-S(O)_(m), wherein the phenyl ring isoptionally substituted with one to two halogen, C₁₋₆ alkoxy, hydroxy ormono- or di-(C₁₋₃ alkyl)amino;

each R₁ is independently:

C₁₋₁₀ alkyl optionally be partially or fully halogenated, and optionallysubstituted with one to three C₃₋₁₀ cycloalkanyl, hydroxy, phenyl,naphthyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl,imidazolyl, pyrazolyl, thienyl, furyl, isoxazolyl or isothiazolyl; eachof the aforementioned being optionally substituted with one to fivegroups selected from halogen, C₁₋₆ alkyl which is optionally partiallyor fully halogenated, C₃₋₈ cycloalkanyl, C₅₋₈ cycloalkenyl, hydroxy,nitrile, C₁₋₃ alkoxy which is optionally partially or fully halogenatedor NH₂C(O), mono- or di(C₁₋₃alkyl)amino, and mono- ordi(C₁₋₃alkyl)aminocarbonyl;

cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, orcycloheptyloxy each being optionally partially or fully halogenated andoptionally substituted with one to three C₁₋₃ alkyl groups optionallypartially or fully halogenated, CN, hydroxyC₁₋₃alkyl or aryl; or ananalog of such cycloalkyl group wherein one to three ring methylenegroups are independently replaced by O, S(O)_(m), CHOH,>C═O,>C═S or NH;

phenyloxy or benzyloxy each being optionally partially or fullyhalogenated and optionally substituted with one to three C₁₋₃ alkylgroups optionally partially or fully halogenated, CN, hydroxyC₁₋₃alkylor aryl; or an analog of such cycloaryl group wherein one to two ringmethyne groups are independently replaced by N;

cyclopropanyl, cyclobutanyl, cyclopentanyl, cyclohexanyl, cycloheptanyl,bicyclopentanyl, bicyclohexanyl or bicycloheptanyl, each beingoptionally partially or fully halogenated and optionally substitutedwith one to three C₁₋₃ alkyl groups optionally partially or fullyhalogenated, CN, hydroxyC₁₋₃alkyl or aryl; or an analog of suchcycloalkyl group wherein one to three ring methylene groups areindependently replaced by O, S(O)_(m), CHOH,>C═O,>C═S or NH;

C₃₋₁₀ branched or unbranced alkenyl each being optionally partially orfully halogenated, and optionally be substituted with one to three C₁₋₅branched or unbranched alkyl, phenyl, naphthyl, pyridinyl, pyrimidinyl,pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl,isoxazolyl or isothiazolyl, each of the aforementioned being substitutedwith zero to five halogen, C₁₋₆ alkyl which is optionally partially orfully halogenated, cyclopropanyl, cyclobutanyl, cyclopentanyl,cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl andbicycloheptanyl, hydroxy, nitrile, C₁₋₃ alkyloxy which is optionallypartially or fully halogenated, NH₂C(O), mono- ordi(C₁₋₃alkyl)aminocarbonyl; the C₃₋₁₀ branched or unbranced alkenylbeing optionally interrupted by one or more heteroatoms chosen from O, Nand S(O)_(m);

cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl,cycloheptadienyl, bicyclohexenyl or bicycloheptenyl, wherein suchcycloalkenyl group is optionally substituted with one to three C₁₋₃alkyl groups;

nitrile, halogen;

methoxycarbonyl, ethoxycarbonyl and propoxycarbonyl;

silyl containing three C₁₋₄ alkyl groups optionally partially or fullyhalogenated;

C₃₋₆ alkynyl branched or unbranched carbon chain optionally partially orfully halogenated, wherein one or more methylene groups are optionallyreplaced by O, NH or S(O)_(m) and wherein said alkynyl group isoptionally independently substituted with one to two oxo groups,pyrrolidinyl, pyrrolyl, one or more C₁₋₄ alkyl optionally substituted byone or more halogen atoms, nitrile, morpholino, piperidinyl,piperazinyl, imidazolyl, phenyl, pyridinyl, tetrazolyl, or mono- ordi(C₁₋₃alkyl)amino optionally substituted by

one or more halogen atoms;

each R₂, R_(4,) and R₅ is

a C₁₋₆ branched or unbranched alkyl optionally partially or fullyhalogenated, acetyl, aroyl, C₁₋₄ branched or unbranched alkoxy, eachbeing optionally partially or fully halogenated, halogen, nitrile,methoxycarbonyl, C₁₋₃ alkyl-S(O)_(m) optionally partially or fullyhalogenated, or phenylsulfonyl;

C₁₋₆ alkoxy, hydroxy, amino, or mono- or di-(C₁₋₄ alkyl)amino, nitrile,halogen;

OR₆;

nitro; or

mono- or di-(C₁₋₄ alkyl)amino-S(O)₂ optionally partially or fullyhalogenated, or H₂NSO₂;

each R₃ is independently:

phenyl, naphthyl, morpholinyl, pyridinyl, pyrimidinyl, pyrazinyl,pyridazinyl, pyrrolyl, pyrrolidinyl, imidazolyl, pyrazolyl, thiazolyl,oxazoyl, triazolyl, tetrazolyl, thienyl, furyl, tetrahydrofuryl,isoxazolyl, isothiazolyl, quinolinyl, isoquinolinyl, indolyl,benzimidazolyl, benzofuranyl, benzoxazolyl, benzisoxazolyl,benzpyrazolyl, benzothiofuranyl, cinnolinyl, pterindinyl, phthalazinyl,naphthypyridinyl, quinoxalinyl, quinazolinyl, purinyl or indazolyl, eachof the aforementioned is optionally substituted with one to threephenyl, naphthyl, heterocycle or heteroaryl as hereinabove described inthis paragraph, C₁₋₆ branched or unbranched alkyl which is optionallypartially or fully halogenated, cyclopropanyl, cyclobutanyl,cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl,bicyclohexanyl, bicycloheptanyl, phenyl C₁₋₅ alkyl, naphthyl C₁₋₅ alkyl,halogen, hydroxy, oxo, nitrile, C₁₋₃ alkyloxy optionally partially orfully halogenated, phenyloxy, naphthyloxy, heteroaryloxy orheterocyclicoxy wherein the heterocyclic or heteroaryl moiety is ashereinabove described in this paragraph, nitro, amino, mono- ordi-(C₁₋₃alkyl)amino, phenylamino, naphthylamino, heteroaryl orheterocyclic amino wherein the heteroaryl heterocyclic moiety is ashereinabove described in this paragraph, NH₂C(O), a mono- ordi-(C₁₋₃alkyl) aminocarbonyl, C₁₋₅ alkyl-C(O)—C₁₋₄ alkyl, amino-C₁₋₅alkyl, mono- or di-(C₁₋₃alkyl)amino-C₁₋₅ alkyl, amino-S(O)₂,di-(C₁₋₃alkyl)amino-S(O)₂, R₇—C₁₋₅ alkyl, R₈—C₁₋₅ alkoxy, R₉—C(O)—C₁₋₅alkyl, R₁₀—C₁₋₅ alkyl (R₁₁)N, carboxy-mono- or di-(C₁₋₅alkyl)-amino;

a fused aryl selected from benzocyclobutanyl, indanyl, indenyl,dihydronaphthyl, tetrahydronaphthyl, benzocycloheptanyl andbenzocycloheptenyl, or a fused heteroaryl selected fromcyclopentenopyridinyl, cyclohexanopyridinyl, cyclopentanopyrimidinyl,cyclohexanopyrimidinyl, cyclopentanopyrazinyl, cyclohexanopyrazinyl,cyclopentanopyridazinyl, cyclohexanopyridazinyl, cyclopentanoquinolinyl,cyclohexanoquinolinyl, cyclopentanoisoquinolinyl,cyclohexanoisoquinolinyl, cyclopentanoindolyl, cyclohexanoindolyl,cyclopentanobenzimidazolyl, cyclohexanobenzimidazolyl,cyclopentanobenzoxazolyl, cyclohexanobenzoxazolyl,cyclopentanoimidazolyl, cyclohexanoimidazolyl, cyclopentanothienyl andcyclohexanothienyl; wherein the fused aryl or fused heteroaryl ring isindependently substituted with zero to three phenyl, naphthyl,pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl,pyrazolyl, thienyl, furyl, isoxazolyl, isothiazolyl, C₁₋₆ alkyl which isoptionally partially or fully halogenated, halogen, nitrile, C₁₋₃alkyloxy which is optionally partially or fully halogenated, phenyloxy,naphthyloxy, heteroaryloxy or heterocyclicoxy wherein the heteroaryl orheterocyclic moiety is as hereinabove described in this paragraph,nitro, amino, mono- or di-(C₁₋₃alkyl)amino, phenylamino, naphthylamino,heteroaryl or heterocyclic amino wherein the heteroaryl or heterocyclicmoiety is as hereinabove described in this paragraph, NH₂C(O), mono- ordi-(C₁₋₃alkyl)aminocarbonyl, C₁₋₄ alkyl-OC(O), C₁₋₅ alkyl-C(O)—C₁₋₄alkyl, amino-C₁₋₅ alkyl, mono- or di-(C₁₋₃)alkylamino-C₁₋₅ alkyl,R₁₂—C₁₋₅ alkyl, R₁₃—C₁₋₅ alkoxy, R₁₄—C(O)—C₁₋₅ alkyl or R₁₅—C₁₋₅alkyl(R₁₆)N; cyclopropanyl, cyclobutanyl, cyclopentanyl, cyclohexanyl,cycloheptanyl, bicyclopentanyl, bicyclohexanyl or bicycloheptanyl, eachbeing optionally partially or fully halogenated and optionallysubstituted with one to three C₁₋₃ alkyl groups, or an analog of suchcycloalkyl group wherein one to three ring methylene groups areindependently replaced by O, S, CHOH,>C═O,>C═S or NH;

cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl,cycloheptadienyl, bicyclohexenyl or bicycloheptenyl, each optionallysubstituted with one to three C₁₋₃ alkyl groups;

C₁₋₄ alkyl-phenyl-C(O)—C₁₋₄ alkyl-, C₁₋₄ alkyl-C(O)—C₁₋₄ alkyl- or C₁₋₄alkyl-phenyl-S(O)_(m)—C₁₋₄ alkyl-;

C₁₋₆ alkyl or C₁₋₆ branched or unbranched alkoxy each of which isoptionally partially or fully halogenated or optionally substituted withR₁₇;

OR₁₈ or C₁₋₆ alkyl optionally substituted with OR₁₈;

amino or mono- or di-(C₁₋₅alkyl)amino optionally substituted with R₁₉;

R₂₀C(O)N(R₂₁)—, R₂₂O— or R₂₃R₂₄NC(O)—; R₂₆(CH₂)_(m)C(O)N(R₂₁)— orR₂₆C(O)(CH₂)_(m)N(R₂₁)—;

C₂₋₆alkenyl substituted by R₂₃R₂₄NC(O)—;

C₂₋₆ alkynyl branched or unbranched carbon chain, optionally partiallyor fully halogenated, wherein one or more methylene groups areoptionally replaced by O, NH, S(O)_(m) and wherein said alkynyl group isoptionally independently substituted with one to two oxo groups,pyrroldinyl, pyrrolyl, morpholinyl, piperidinyl, piperazinyl,imidazolyl, phenyl, pyridinyl, tetrazolyl one or more C₁₋₄ alkyloptionally substituted by one or more halogen atoms, nitrile,morpholino, piperidinyl, piperazinyl, imidazolyl, phenyl, pyridinyl,tetrazolyl, or mono- or di(C₁₋₄ alkyl)amino optionally substituted byone or more halogen atoms; or

aroyl;

R₆ is a:

C₁₋₄ alkyl optionally partially or fully halogenated and optionallysubstituted with R₂₆;

each R₇, R₈, R₉, R₁₀, R₁₂, R₁₃ R₁₄, R_(15,) R₁₇, R₁₉, R₂₅ and R₂₆ isindependently nitrile, phenyl, morpholino, piperidinyl, piperazinyl,imidazolyl, pyridinyl, tetrazolyl, amino or mono- or di-(C₁₋₄alkyl)aminooptionally partially or fully halogenated;

each R₁₁ and R₁₆ is independently:

hydrogen or C₁₋₄ alkyl optionally partially or fully halogenated;

R₁₈ is independently:

hydrogen or a C₁₋₄ alkyl optionally independently substituted with oxoor R₂₅;

R₂₀ is independently:

C₁₋₁₀ alkyl optionally partially or fully halogenated, phenyl, orpyridinyl;

R₂₁ is independently:

hydrogen or C₁₋₃ alkyl optionally partially or fully halogenated;

each R₂₂, R₂₃ and R₂₄ is independently:

hydrogen, C₁₋₆ alkyl optionally partially or fully halogenated, saidC₁₋₆ alkyl is optionally interrupted by one or more O, N or S, said C₁₋₆alkyl also being independently optionally substituted by mono- ordi-(C₁₋₃alkyl)aminocarbonyl, phenyl, pyridinyl, amino or mono-ordi-(C₁₋₄alkyl)amino each of which is optionally partially or fullyhalogenated and optionally substituted with mono- ordi-(C₁₋₃alkyl)amino;

or R₂₃ and R₂₄ taken together optionally form a heterocyclic orheteroaryl ring;

m=0, 1 or 2;

W is O or S and

pharmaceutically acceptable derivatives thereof.

In another embodiment of the invention there is provided compounds ofthe formula(II) as described immmediately above, and wherein

G is:

phenyl, naphthyl, benzocyclobutanyl, dihydronaphthyl,tetrahydronaphthyl, benzocycloheptanyl, benzocycloheptenyl, indanyl,indenyl;

pyridinyl, pyridonyl, quinolinyl, dihydroquinolinyl, tetrahydroquinoyl,isoquinolinyl, tetrahydroisoquinoyl, pyridazinyl, pyrimidinyl,pyrazinyl, benzimidazolyl, benzthiazolyl, benzoxazolyl, benzofuranyl,benzothiophenyl, benzpyrazolyl, dihydrobenzofuranyl,dihydrobenzothiophenyl, benzooxazolonyl, benzo[1,4]oxazin-3-onyl,benzodioxolyl, benzo[1,3]dioxol-2-onyl, benzofuran-3-onyl,tetrahydrobenzopyranyl, indolyl, indolinyl, indolonyl, indolinonyl,phthalimidyl;

oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl,piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, dioxanyl,tetramethylene sulfonyl, tetramethylene sulfoxidyl, oxazolinyl,thiazolinyl, imidazolinyl, tertrahydropyridinyl, homopiperidinyl,pyrrolinyl, tetrahydropyrimidinyl, decahydroquinolinyl,decahydroisoquinolinyl, thiomorpholinyl, thiazolidinyl, dihydrooxazinyl,dihydropyranyl, oxocanyl, heptacanyl, thioxanyl or dithianyl;

wherein G is substituted by one or more R₁, R₂ or R₃;

In another embodiment of the invention there is provided compounds ofthe formula(II) as described immediately above, and wherein

G is phenyl, pyridinyl, pyridonyl, naphthyl, quinolinyl, isoquinolinyl,pyrazinyl, benzimidazolyl, benzoxazolyl, benzofuranyl, benzothiophenyl,benzpyrazolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, indanyl,indenyl, indolyl, indolinyl, indolonyl or indolinonyl, wherein G issubstituted by one or more R₁, R₂ or R₃;

Ar is:

naphthyl, quinolinyl, isoquinolinyl, tetrahydronaphthyl,tetrahydroquinolinyl, tetrahydroisoquinolinyl, indanyl, indenyl orindolyl each being optionally substituted by one or more R₄ or R₅groups;

X is:

phenyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, pyridinyl,pyrimidinyl, pyridinonyl, dihydropyridinonyl, maleimidyl,dihydromaleimidyl, piperdinyl, piperazinyl, pyridazinyl or pyrazinyl

Y is:

a bond or

a C₁₋₄ saturated or unsaturated carbon chain wherein one of the carbonatoms is optionally replaced by O, N, or S(O)_(m) and wherein Y isoptionally independently substituted with one to two oxo groups, phenylor one or more C₁₋₄ alkyl optionally substituted by one or more halogenatoms;

Z is:

phenyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, imidazolyl,furanyl, thienyl, dihydrothiazolyl, dihydrothiazolyl sulfoxidyl,pyranyl, pyrrolidinyl which are optionally substituted with one to threenitrile, C₁₋₃ alkyl, C₁₋₃ alkoxy, amino, mono- or di-(C₁₋₃ alkyl)amino,CONH₂ or OH;

tetrahydropyranyl, tetrahydrofuranyl, 1,3-dioxolanonyl, 1,3-dioxanonyl,1,4-dioxanyl, morpholinyl, thiomorpholinyl, thiomorpholino sulfoxidyl,piperidinyl, piperidinonyl, piperazinyl, tetrahydropyrimidonyl,pentamethylene sulfidyl, pentamethylene sulfoxidyl, pentamethylenesulfonyl, tetramethylene sulfidyl, tetramethylene sulfoxidyl ortetramethylene sulfonyl which are optionally substituted with one tothree nitrile, C₁₋₃ alkyl, C₁₋₃ alkoxy, amino, mono- or di-(C₁₋₃alkyl)amino, CONH₂, or OH; nitrile, C₁₋₆ alkyl-S(O)_(m), halogen,hydroxy, C₁₋₄ alkoxy, amino, mono- or di-(C₁₋₆ alkyl)amino, mono- ordi-(C₁₋₃ alkyl)aminocarbonyl or NH₂C(O);

each R₁ is independently:

C₃₋₆ alkyl optionally partially or fully halogenated, and optionallysubstituted with one to three C₃₋₆cycloalkyl, phenyl, thienyl, furyl,isoxazolyl or isothiazolyl; each of the aforementioned being optionallysubstituted with one to three groups selected from halogen, C₁₋₃ alkylwhich is optionally partially or fully halogenated, hydroxy, nitrile orC₁₋₃alkoxy which is optionally partially or fully halogenated;

cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, bicyclopentanyl orbicyclohexanyl, each being optionally partially or fully halogenated andoptionally substituted with one to three C₁₋₃ alkyl groups optionallypartially or fully halogenated, CN, hydroxyC₁₋₃alkyl or phenyl; or ananalog of such cycloalkyl group wherein one to three ring methylenegroups are independently replaced by O, S, CHOH,>C═O,>C═S or NH; or

silyl containing three C₁₋₄ alkyl groups optionally partially or fullyhalogenated;

R₂ is independently:

halogen, C₁₋₃ alkoxy, C₁₋₃ alkyl-S(O)_(m) optionally partially or fullyhalogenated, phenylsulfonyl or nitrile;

R₃ is independently:

phenyl, morpholino, pyridinyl, pyrimidinyl, pyrazinyl, pyrrolyl,pyrrolylidinyl, imidazolyl, pyrazolyl, each being optionally substitutedwith one to three phenyl, naphthyl, heterocycle or heteroaryl ashereinabove described in this paragraph, C₁₋₆ alkyl which is optionallypartially or fully halogenated, cyclopropanyl, cyclobutanyl,cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl,bicyclohexanyl, bicycloheptanyl, phenyl C₁₋₅ alkyl, naphthyl C₁₋₅ alkyl,halogen, oxo, hydroxy, nitrile, C₁₋₃ alkyloxy optionally partially orfully halogenated, phenyloxy, naphthyloxy, heteroaryloxy orheterocyclicoxy wherein the heteroaryl or heterocyclic moiety is ashereinabove described in this paragraph, nitro, amino, mono- ordi-(C₁₋₃alkyl)amino, phenylamino, naphthylamino, heteroaryl orheterocyclic amino wherein the heteroaryl or heterocyclic moiety is ashereinabove described in this paragraph, NH₂C(O), a mono- ordi-(C₁₋₃alkyl)aminocarbonyl, C₁₋₅ alkyl-C(O)—C₁₋₄ alkyl, mono- ordi-(C₁₋₃alkyl)amino, mono- or di-(C₁₋₃)alkylamino-C₁₋₅ alkyl, mono- ordi-(C₁₋₃alkyl)amino-S(O)₂, R₇—C₁₋₅ alkyl, R₈—C₁₋₅ alkoxy, R₉—C(O)—C₁₋₅alkyl, R₁₀—C₁₋₅ alkyl(R₁₁)N, carboxy-mono- or di-(C₁₋₅)-alkyl-amino;

C₁₋₃ alkyl or C₁₋₄ alkoxy each being optionally partially or fullyhalogenated or optionally substituted with R₁₇;

OR₁₈ or C₁₋₆ alkyl optionally substituted with OR₁₈; amino or mono- ordi-(C₁₋₅ alkyl)amino optionally substituted with R₁₉;

R₂₀C(O)N(R₂₁)—, R₂₂O—; R₂₃R₂₄NC(O)—; R₂₆CH₂C(O)N(R₂₁)— orR₂₆C(O)CH₂N(R₂₁)—; C₂₋₄alkenyl substituted by R₂₃R₂₄NC(O)—; or

C₂₋₄ alkynyl branched or unbranched carbon chain optionally partially orfully halogenated and optionally independently substituted with one totwo oxo groups, pyrroldinyl, pyrrolyl, morpholinyl, piperidinyl,piperazinyl, imidazolyl, phenyl, pyridinyl, tetrazolyl or one or moreC₁₋₄ alkyl optionally substituted by one or more halogen atoms; and

R₂₃ and R₂₄ taken together optionally form imidazolyl, piperidinyl,morpholinyl, piperazinyl or a pyridinyl ring.

In yet another embodiment of the invention there is provided compoundsof the formula(II) as described immediately above, and wherein:

G is phenyl, pyridinyl, pyridonyl, naphthyl, quinolinyl, isoquinolinyl,pyrazinyl, benzothiophenyl, dihydrobenzoturanyl, dihydrobenzothiophenyl,indanyl, indolyl, indolinyl, indolonyl or indolinonyl, wherein G issubstituted by one or more R₁, R₂ or R₃;

Ar is naphthyl;

X is

phenyl, imidazolyl, pyridinyl, pyrimidinyl, piperdinyl, piperazinyl,pyridazinyl or pyrazinyl each being optionally independently substitutedwith one to three C₁₋₄ alkyl, C₁₋₄alkoxy, hydroxy, nitrile, amino, mono-or di-(C₁₋₃ alkyl)amino, mono- or di-(C₁₋₃ alkylamino)carbonyl, NH₂C(O),C₁₋₆ alkyl-S(O)_(m) or halogen;

Y is:

a bond or

a C₁₋₄ saturated carbon chain wherein one of the carbon atoms isoptionally replaced by O, N or S and wherein Y is optionallyindependently substituted with an oxo group;

Z is:

phenyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, imidazolyl,dihydrothiazolyl, dihydrothiazolyl sulfoxide, pyranyl or pyrrolidinylwhich are optionally substituted with one to two C₁₋₂ alkyl or C₁₋₂alkoxy;

tetrahydropyranyl, morpholinyl, thiomorpholinyl, thiomorpholinosulfoxidyl, piperidinyl, piperidinonyl, piperazinyl ortetrahydropyrimidonyl which are optionally substituted with one to twoC₁₋₂ alkyl or C₁₋₂ alkoxy; or

C₁₋₃ alkoxy;

each R₁ is independently:

C₃₋₅ alkyl optionally partially or fully halogenated, and optionallysubstituted with phenyl substituted with zero to three halogen, C₁₋₃alkyl which is optionally partially or fully halogenated, hydroxy,nitrile or C₁₋₃alkoxy which is optionally partially or fullyhalogenated;

cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, bicyclopentanyl orbicyclohexanyl, each being optionally partially or fully halogenated andoptionally substituted with one to three C₁₋₃ alkyl groups optionallypartially or fully halogenated, CN, hydroxyC₁₋₃alkyl or phenyl; and ananalog of cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl,bicyclopentanyl or bicyclohexanyl wherein one ring methylene group isreplaced by O; and

silyl containing three C₁₋₂ independently alkyl groups optionallypartially or fully halogenated;

each R₂ is independently:

bromo, chloro, fluoro, methoxy, methylsulfonyl or nitrile;

each R₃ is independently:

phenyl, morpholino, pyridinyl, pyrimidinyl, pyrrolylidinyl,2,5-pyrrolidin-dionyl, imidazolyl, pyrazolyl, each of the aforementionedis optionally substituted with one to three C₁₋₃ alkyl which isoptionally partially or fully halogenated, halogen, oxo, hydroxy,nitrile and C₁₋₃ alkyloxy optionally partially or fully halogenated;

C₁₋₃ alkyl or C₁₋₃ alkoxy each being optionally partially or fullyhalogenated or optionally substituted with R₁₇;

OR₁₈ or C₁₋₃ alkyl optionally substituted with OR₁₈; amino or mono- ordi-(C₁₋₃ alkyl)amino optionally substituted with R₁₉;

R₂₀C(O)N(R₂₁)—, R₂₂O—; R₂₃R₂₄NC(O)—; R₂₆CH₂C(O)N(R₂₁)— orR₂₆C(O)CH₂N(R₂₁)—;

C₂₋₄ alkenyl substituted by R₂₃R₂₄NC(O)—; or

C₂₋₄ alkynyl substituted with pyrroldinyl or pyrrolyl; and

R₂₃ and R₂₄ taken together optionally form morpholino.

In yet still another embodiment of the invention there is providedcompounds of the formula(II) as described immediately above, and wherein

G is phenyl, pyridinyl, pyridonyl, naphthyl, quinolinyl, isoquinolinyl,dihydrobenzofuranyl, indanyl, indolinyl, indolonyl, or indolinonyl,wherein G is substituted by one or more R₁, R₂ or R₃;

Ar is 1-naphthyl;

X is:

phenyl, imidazolyl, pyridinyl, pyrimidinyl, piperdinyl, piperazinyl,pyridazinyl or pyrazinyl;

Y is:

a bond or —CH₂—, —CH₂CH₂—, —C(O)—, —O—, —S—, —NH—CH₂CH₂CH₂—, —N(CH₃)—,or —NH—;

each R₁ is independently:

C₃₋₅ alkyl optionally partially or fully halogenated, and optionallysubstituted with phenyl;

cyclopropyl, cyclopentanyl, cyclohexanyl and bicyclopentanyl optionallysubstituted with one to three methyl groups optionally partially orfully halogenated, CN, hydroxymethyl or phenyl; or 2-tetrahydrofuranylsubstituted by methyl; or trimethyl silyl;

each R₃ is independently:

phenyl, morpholinyl, pyridinyl, pyrimidinyl, pyrrolylidinyl,2,5-pyrrolidin-dionyl, imidazolyl or pyrazolyl, wherein any of theaforementioned is optionally substituted with C₁₋₂ alkyl which isoptionally partially or fully halogenated;

C₁₋₃ alkyl or C₁₋₃ alkoxy each being optionally partially or fullyhalogenated or optionally substituted with diethylamino;

OR₁₈ or C₁₋₃ alkyl optionally substituted with OR₁₈;

amino or mono- or di-(C₁₋₃ alkyl)amino optionally substituted with R₁₉;

CH₃C(O)NH—, R₂₂O—; R₂₃R₂₄NC(O)—; R₂₆CH₂C(O)N(R₂₁)— or R₂₆C(O)CH₂N(R₂₁)—;

C₂₋₄alkenyl substituted by R₂₃R₂₄NC(O)—; or

C₂₋₄ alkynyl substituted with pyrroldinyl or pyrrolyl;

R₂₃ and R₂₄ are H or R₂₃ and R₂₄ taken together optionally formmorpholino; and R₂₆ is morpholino.

In another embodiment of the invention there is provided of theformula(II) as described immediately above, and wherein

G is

phenyl, pyridinyl or naphthyl wherein G is substituted by one or moreR₁, R₂ or R₃;

X is:

imidazolyl or pyridinyl;

Y is:

—CH₂₋, —NH—CH₂CH₂CH₂— or —NH—;

Z is morpholino;

each R₁ is independently:

tert-butyl, sec-butyl, tert-amyl or phenyl;

R₂ is chloro;

R₃ is independently:

methyl, methoxy, methoxymethyl, hydroxypropyl, acetamide, morpholino ormorpholinocarbonyl.

In yet a further embodiment of the invention there is provided of theformula(II) as described immediately above, and wherein X is pyridinyl.

In yet a further embodiment of the invention there is provided of theformula(II) as described immediately above, and wherein the pyridinyl isattached to Ar via the 3-pyridinyl position.

The following are representative compounds of the formula(II):

1-(3-Cyano-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea

1-(3-Fluoro-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea

1-(4-Chloro-2-trifluoromethyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea

1-(2-Chloro-5-trifluoromethyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea

1-(3,4-Dimethyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea

1-(3,4-Iodo-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea

1-[4-(6-Morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-3-m-tolyl-urea

1-(4-Methylsulfanyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea

1-(3-Chloro-4-methyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea

1-(4-Chloro-3-nitro-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea

1-(2,5-Dichloro-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea

1-[4-(6-Morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-3-naphthalen-2-yl-urea

1-[4-(6-Morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-3-phenyl-urea

1-(3-Chloro-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea

1-(4-Chloro-3-trifluoromethyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea

1-[4-(6-Morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-3-(2,4,6-trichloro-phenyl)-urea

1-(2-Methyl-3-nitro-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea

1-(4-Methyl-2-nitro-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea

1-(2,3-Dichloro-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea

1-(2-Methoxy-5-methyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea

1-(2-Chloro-6-methyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea

1-(2,4-Dichloro-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea

1-(4-Methyl-3-nitro-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea

1-(2,4-Dimethyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea

1-(2,3-Dimethyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea

1-(4-Cyano-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea

1-[4-(6-Morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-3-(3,4,5-trimethoxy-phenyl)-urea

1-Biphenyl-4-yl-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea

1-(2,5-Difluoro-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea

1-(3-Chloro-2-methoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea

1-(2-Fluoro-3-trifluoromethyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea

1-(4-Benzyloxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea

1-(2-Methylsulfanyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea

1-(2-Fluoro-6-trifluoromethyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea

1-(4-Fluoro-3-trifluoromethyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea

1-[4-(6-Morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-3-(2,4,5-trimethyl-phenyl)-urea

1-[4-(6-Morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-3-(4-trifluoromethyl-phenyl)-urea

1-(3-Methylsulfanyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea

1-(2-Methoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea

1-(2-Fluoro-5-trifluoromethyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea

1-(4-Methoxy-2-methyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea

1-(2-Fluoro-5-nitro-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea

1-(4-Ethoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea

1-(2,5-Dimethoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea

1-(4,5-Dimethyl-2-nitro-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea

1-(5-Chloro-2-methyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea

1-(2-Isopropyl-6-methyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea

1-(2-Difluoromethoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea

1-(4-Isopropyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea

1-(4-Methoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea

1-(3-Ethyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea

1-(2-Ethoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea

1-(4-Butoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea

4-{3-[4-(6-Morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-ureido}-benzoicacid ethyl ester

1-(4-Butyl-2-methyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea

1-(2,6-Dibromo-4-isopropyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea

1-(3-Methoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea

1-[4-(6-Morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-3-(4-trifluoromethylsulfanyl-phenyl)-urea

5-{3-[4-(6-Morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-ureido}-isophthalicacid dimethyl ester

1-(3-Cyclopentyloxy-4-methoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea

3-{3-[4-(6-Morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-ureido}-benzoicacid ethyl ester

1-(5-tert-Butyl-2-hydroxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea

1-(2-Hydroxymethyl-4-phenyl-cyclohexyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea

1-(2-Methylsulfanyl-5-trifluoromethyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea

1-[4-(6-Morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-3-(4-pentyloxy-biphenyl-3-yl)-urea

4-Methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-ureido{-benzoicacid methyl ester

1-(2,5-Diethoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea

1-Benzothiazol-6-yl-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea

N-(2,5-Diethoxy-4-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-ureido}-phenyl)-benzamide

1-[4-(6-Morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-3-(3-phenoxy-phenyl)-urea

1-(5-Ethanesulfonyl-2-methoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea

4-Methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-ureido}-N-phenyl-benzamide

1-(2-Methyl-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea

1-(2,3-Dimethyl-1H-indol-5-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea

N-Butyl-4-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-ureido}-benzenesulfonamide

1-[3-(2-Methyl-[1,3]dioxolan-2-yl)-phenyl]-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea

1-(3-Methoxy-5-trifluoromethyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea

1-(2,4-Dimethoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea

1-(2-Methyl-4-nitro-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea

1-(2-Methoxy-4-nitro-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea

1-(4-Chloro-2-nitro-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea

1-(5-Chloro-2-methoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea

1-(3,5-Dimethoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea

1-[4-(6-Morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-3-(4-trifluoromethoxy-phenyl)-urea

1-[4-(6-Morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-3-(3-trifluoromethylsulfanyl-phenyl)-urea

1-[4-(6-Morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-3-(2-phenoxy-phenyl)-urea

1-(2-Methoxy-5-nitro-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea

1-(5-Chloro-2,4-dimethoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea

1-(3,5-Bis-trifluoromethyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea

1-(2-tert-Butyl-5-methyl-pyridin-4-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea

1-(3-Methyl-naphthalen-2-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea

1-(3-tert-Butyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea

1-(4-Methyl-biphenyl-3-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea

1-(4-tert-Butyl-biphenyl-2-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea

1-(5-Chloro-2,4-dimethoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea

1-(5-Isopropyl-2-methyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea

1-(5-sec-Butyl-2-methoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea

1-(5-tert-Butyl-2-methoxy-3-propyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea

1-(5-tert-Butyl-2-methoxymethyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea

1-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea

1-(5-tert-Butyl-2-methyl-phenyl)-3-(4-{6-[(3-methoxy-propyl)-methyl-amino]-pyridin-3-yl}-naphthalen-1-yl)-urea

1-(5-tert-Butyl-2-methyl-phenyl)-3-[4-(4-morpholin-4-ylmethyl-imidazol-1-yl)-naphthalen-1-yl]-urea

1-(5-tert-Butyl-2-methyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea

1-(5-tert-Butyl-2-methyl-phenyl)-3-{4-[6-(3-methoxy-propylamino)-pyridin-3-yl]-naphthalen-1-yl}-urea

1-(5-tert-Butyl-2-methyl-pyridin-3-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea

1-(5-tert-Butyl-2-morpholin-4-yl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea

1-(6-tert-Butyl-2-chloro-3-methyl-pyridin-4-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea

1-[4-(6-Morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-3-(3-trifluoromethyl-phenyl)-urea

1-[4-(6-Morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-3-(4-trifluoromethoxy-phenyl)-urea

1-[5-(1,1-Dimethyl-propyl)-2-methoxy-phenyl]-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea

1-[5-tert-Butyl-2-(1H-pyrazol-4-yl)-phenyl]-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl-)-naphthalen-1-yl]-urea

1-[5-tert-Butyl-2-(2-methyl-pyrimidin-5-yl)-phenyl]-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea

1-[5-tert-Butyl-2-(3-hydroxy-propyl)-phenyl]-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea

1-[5-tert-Butyl-2-(3-morpholin-4-yl-3-oxo-propyl)-phenyl]-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea

1-[5-tert-Butyl-2-(morpholine-4-carbonyl)-phenyl]-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea

N-(5-tert-Butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-ureido}-phenyl)-acetamide

and the pharmaceutically acceptable derivatives thereof.

In addtion to the abovementioned representative compounds the followingprophetic compounds of the formula(II) may be made by the generalmethods described hereinbelow:

1-[4-(6-{[Bis-(2-cyano-ethyl)-amino]-methyl}-pyridin-3-yl)-naphthalen-1-yl]-3-(5-tert-butyl-2-methoxy-phenyl)-urea

1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[4-(2-methyl-3-oxo-piperazin-1-ylmethyl)-phenyl]-naphthalen-1-yl}-urea

1-[4-(6-{[Bis-(2-methoxy-ethyl)-amino]-methyl}-pyridin-3-yl)-naphthalen-1-yl]-3-(5-tert-butyl-2-methoxy-phenyl)-urea

1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(2-methyl-3-oxo-piperazin-1-ylmethyl)-pyridin-3-yl]-naphthalen-1-yl}-urea

1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(1-oxo-114-thiomorpholin-4-ylmethyl)-pyridin-3-yl]-naphthalen-1-yl}-urea

1-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(6-thiomorpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea

1-(5-tert-Butyl-2-methyl-phenyl)-3-{4-[6-(1-oxo-114-thiomorpholin-4-ylmethyl)-pyridin-3-yl]-naphthalen-1-yl}-urea

1-(5-tert-Butyl-2-methyl-phenyl)-3-{4-[6-(2-methyl-3-oxo-piperazin-1-ylmethyl)-pyridin-3-yl]-naphthalen-1-yl}-urea

1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[4-(1-oxo-11-thiomorpholin-4-ylmethyl)-phenyl]-naphthalen-1-yl}-urea

1-[4-(4-{[Bis-(2-cyano-ethyl)-amino]-methyl}-phenyl)-naphthalen-1-yl]-3-(5-tert-butyl-2-methoxy-phenyl)-urea

1-(2-Methoxy-5-pentafluoroethyl-phenyl)-3-[4-(4-morpholin-4-ylmethyl-piperidin-1-yl)-naphthalen-1-yl]-urea

1-(2-Methoxy-5-trifluoromethyl-pyridin-3-yl)-3-{4-[2-(4-oxo-piperidin-1-ylmethyl)-pyrimidin-5-yl]-naphthalen-1-yl}-urea

1-(2-Methoxy-5-trimethylsilanyl-phenyl)-3-{4-[4-(tetrahydro-pyran-4-ylamino)-phenyl]-naphthalen-1-yl}-urea

1-(3-Methoxy-naphthalen-2-yl)-3-[4-(4-morpholin-4-ylmethyl-piperidin-1-yl)-naphthalen-1-yl]-urea

1-(3-Methyl-naphthalen-2-yl)-3-[4-(4-morpholin-4-ylmethyl-phenyl)-naphthalen-1-yl]-urea

1-(3-tert-Butyl-5-methanesulfinyl-phenyl)-3-{4-[6-(1-methyl-piperidin-4-ylmethyl)-pyridin-3-yl]-naphthalen-1-yl}-urea

1-(3-tert-Butyl-phenyl)-3-[4-(3-pyridin-3-yl-propoxy)-naphthalen-1-yl]-urea

1-(3-tert-Butyl-phenyl)-3-[4-(4-morpholin-4-ylmethyl-phenyl)-naphthalen-1-yl]-urea

1-(4-Methoxy-biphenyl-3-yl)-3-{4-[4-(tetrahydro-pyran-4-ylmethyl)-imidazol-1-yl]-naphthalen-1-yl}-urea

1-(4-Methyl-biphenyl-3-yl)-3-{4-[4-(2-pyridin-4-yl-ethyl)-piperazin-1-yl]-naphthalen-1-yl}-urea

1-(4-tert-Butyl-biphenyl-2-yl)-3-[4-(pyridin-4-ylmethoxy)-naphthalen-1-yl]-urea

1-(4-tert-Butyl-biphenyl-2-yl)-3-{4-[2-(1-oxo-114-thiomorpholin-4-ylmethyl)-3H-imidazol-4-yl]-naphthalen-1-yl}-urea

1-(5-tert-Butyl-2-hydroxy-phenyl)-3-[4-(5-morpholin-4-ylmethyl-pyrazin-2-yl)-naphthalen-1-yl]-urea

1-(5-tert-Butyl-2-methoxy-3-propyl-phenyl)-3-{4-[4-(pyrrolidine-1-carbonyl)-phenyl]-naphthalen-1-yl}-urea

1-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(2-morpholin-4-ylmethyl-pyrimidin-5-yl)-naphthalen-1-yl]-urea

1-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(4-thiomorpholin-4-ylmethyl-phenyl)-naphthalen-1-yl]-urea

1-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-phenyl)-naphthalen-1-yl]-urea

1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[4-(tetrahydro-pyran-4-ylamino)-phenyl]-naphthalen-1-yl}-urea

1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(4-methyl-piperazin-1-ylmethyl)-pyridin-3-yl]-naphthalen-1-yl}-urea

1-(5-tert-Butyl-2-methoxy-pyridin-3-yl)-3-{4-[6-(4-oxo-piperidin-1-ylmethyl)-pyridin-3-yl]-naphthalen-1-yl}-urea

1-(5-tert-Butyl-2-methyl-benzooxazol-7-yl)-3-[4-(6-pyridin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea

1-(5-tert-Butyl-2-methyl-phenyl)-3-[4-(4-morpholin-4-ylmethyl-phenyl)-naphthalen-1-yl]-urea

1-(5-tert-Butyl-2-phenoxy-phenyl)-3-{4-[6-(tetrahydro-pyran-4-yloxy)-pyridin-3-yl]-naphthalen-1-yl}-urea

1-(5-tert-Butyl-2-pyrrolidin-1-yl-phenyl)-3-[4-(4-methoxy-6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea

1-(5-tert-Butyl-2-pyrrolidin-1-yl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea

1-(5-tert-Butyl-3-cyano-2-methoxy-phenyl)-3-{4-[2-(2,6-dimethyl-morpholin-4-ylmethyl)-pyrimidin-5-yl]-naphthalen-1-yl}-urea

1-(5-tert-Butyl-4′-dimethylamino-biphenyl-3-yl)-3-[4-(2-morpholin-4-ylmethyl-pyrimidin-5-yl)-naphthalen-1-yl]-urea

1-(6-Methoxy-3,3-dimethyl-indan-5-yl)-3-{4-[4-(morpholine-4-carbonyl)-phenyl]-naphthalen-1-yl}-urea

1-(6-tert-Butyl-2-chloro-3-methyl-pyridin-4-yl)-3-[4-(6-thiomorpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea

1-(6-tert-Butyl-benzo[1,3]dioxol-4-yl)-3-{4-[6-(morpholin-4-ylamino)-pyridin-3-yl]-naphthalen-1-yl}-urea

1-(7-Methoxy-1,4,4-trimethyl-1,2,3,4-tetrahydro-quinolin-6-yl)-3-{4-[6-(tetrahydro-pyran-4-yloxy)-pyridin-3-yl]-naphthalen-1-yl}-urea

1-(7-tert-Butyl-2,4-dimethyl-benzooxazol-5-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea

1-[2-Methoxy-5-(1-methyl-1-phenyl-ethyl)-phenyl]-3-{4-[6-(2-pyridin-4-yl-ethyl)-pyridazin-3-yl]-naphthalen-1-yl}-urea

1-[2-Methoxy-5-(1-methyl-cyclohexyl)-phenyl]-3-{4-[4-(1-methyl-piperidin-4-ylsulfanyl)-phenyl]-naphthalen-1-yl}-urea

1-[2-Methoxy-5-(1-methyl-cyclopropyl)-phenyl]-3-[4-(2-morpholin-4-ylmethyl-pyrimidin-5-yl)-naphthalen-1-yl]-urea

1-[2-Methoxy-5-(2-methyl-tetrahydro-furan-2-yl)-phenyl]-3-[4-(5-morpholin-4-ylmethyl-pyridin-2-yl)-naphthalen-1-yl]-urea

1-[2-Methoxy-5-(3-trifluoromethyl-bicyclo[1.1.1]pent-1-yl)-phenyl]-3-[4-(4-morpholin-4-ylmethyl-phenyl)-naphthalen-1-yl]-urea

1-[3-tert-Butyl-5-(1-methyl-1H-imidazol-4-yl)-phenyl]-3-[4-(5-morpholin-4-ylmethyl-pyridin-2-yl)-naphthalen-1-yl]-urea

1-[3-tert-Butyl-5-(2-pyrrolidin-1-yl-ethyl)-phenyl]-3-{4-[6-(1-methyl-piperidin-4-yloxy)-pyridin-3-yl]-naphthalen-1-yl}-urea

1-[3-tert-Butyl-5-(3-pyrrolidin-1-yl-prop-1-ynyl)-phenyl]-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea

1-[4-(6-Imidazol-1-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-3-[2-methoxy-5-(1-phenyl-cyclopropyl)-phenyl]-urea

1-[5-(1,1-Dimethyl-propyl)-2-methoxy-phenyl]-3-[4-(4-thiomorpholin-4-ylmethyl-phenyl)-naphthalen-1-yl]-urea

1-[5-(1-Cyano-cyclopropyl)-2-methoxy-phenyl]-3-[4-(2-morpholin-4-ylmethyl-pyrimidin-5-yl)-naphthalen-1-yl]-urea

1-[5-(1-Hydroxymethyl-cyclopropyl)-2-methoxy-phenyl]-3-[4-(4-morpholin-4-ylmethyl-phenyl)-naphthalen-1-yl]-urea

1-[5-tert-Butyl-1-(2-diethylamino-ethyl)-2-oxo-1,2-dihydro-pyridin-3-yl]-3-{4-[6-(1-methyl-piperidin-4-yloxy)-pyridin-3-yl]-naphthalen-1-yl}-urea

1-[5-tert-Butyl-2-(1H-pyrazol-4-yl)-phenyl]-3-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-1-yl]-urea

1-[5-tert-Butyl-2-(1H-pyrazol-4-yl)-phenyl]-3-{4-[4-(4-methyl-piperazine-1-carbonyl)-phenyl]-naphthalen-1-yl}-urea

1-[5-tert-Butyl-2-(2,5-dioxo-pyrrolidin-1-yl)-phenyl]-3-{4-[6-(1H-imidazol-2-ylmethyl)-pyridin-3-yl]-naphthalen-1-yl}-urea

1-[5-tert-Butyl-2-(2-methyl-pyrimidin-5-yl)-phenyl]-3-[4-(5-pyridin-4-ylmethyl-pyrudin-2-yl)-naphthalen-1-yl]-urea

1-[5-tert-Butyl-2-(2-morpholin-4-yl-2-oxo-ethoxy)-phenyl]-3-{4-[6-(2-pyridin-4-yl-ethyl)-pyridazin-3-yl]-naphthalen-1-yl}-urea

1-[5-tert-Butyl-2-(2-morpholin-4-yl-2-oxo-ethylamino)-phenyl]-3-{4-[4-(1-methyl-piperidin-4-ylamino)-piperidin-1-yl]-naphthalen-1-yl}-urea

1-[5-tert-Butyl-2-(6-methyl-pyridin-3-yl)-phenyl]-3-{4-[5-(2-pyrrolidin-1-yl-ethyl)-pyridin-2-yl]-naphthalen-1-yl}-urea

1-[5-tert-Butyl-2-methoxy-3-(3-morpholin-4-yl-3-oxo-propenyl)-phenyl]-3-[4-(6-pyrrolidin-1-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea

1-[5-tert-Butyl-3-(2-diethylamino-ethoxy)-2-methoxy-phenyl]-3-{4-[4-(tetrahydro-pyran-4-yloxy)-phenyl]-naphthalen-1-yl}-urea

1-[5-tert-Butyl-3-(2-pyrrolidin-1-yl-ethyl)-benzofuran-7-yl]-3-[4-(4-morpholin-4-ylmethyl-phenyl)-naphthalen-1-yl]-urea

1-[6-tert-Butyl-4-(2-dimethylamino-ethyl)-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl]-3-4-[6-(thiomorpholin-4-ylamino)-pyridin-3-yl]-naphthalen-1-yl}-urea

1-{5-tert-Butyl-2-methoxy-3-[2-(1-methyl-piperidin-4-yloxy)-ethyl]-phenyl}-3-[4-(4-morpholin-4-ylmethyl-phenyl)-naphthalen-1-yl]-urea

2-(4-tert-Butyl-2-{3-[4-(5-pyrrolidin-1-ylmethyl-pyridin-2-yl)-naphthalen-1-yl]-ureido}-phenoxy)-N-methyl-acetamide

2-[4-tert-Butyl-2-(3-{4-[6-(2,6-dimethyl-morpholin-4-ylmethyl)-pyridin-3-yl]-naphthalen-1-yl}-ureido)-phenoxy]-acetamide

3-(5-tert-Butyl-2-methoxy-3-13-[4-(6-pyrrolidin-1-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-ureido}-phenyl)-acrylamide

3-{3-tert-Butyl-5-[3-(4-{4-[2-(1-oxo-114-thiazolidin-3-yl)-ethyl]-phenyl}-naphthalen-1-yl)-ureido]-phenyl}-N,N-dimethyl-propionamide

3-{4-[3-(5-tert-Butyl-2-methoxy-phenyl)-ureido]-naphthalen-1-yl}-benzamide

4-tert-Butyl-2-{3-[4-(2-chloro-4-morpholin-4-ylmethyl-phenyl)-naphthalen-1-yl]-ureido}-benzamide

N-(4-tert-Butyl-2-{3-[4-(6-oxo-1,6-dihydro-pyridin-3-yl)-naphthalen-1-yl]-ureido}-phenyl)-2-morpholin-4-yl-acetamide

N-[3-tert-Butyl-5-(3-{4-[5-(tetrahydro-pyran-4-ylamino)-pyridin-2-yl]-naphthalen-1-yl}-ureido)-phenyl]-2-morpholin-4-yl-acetamide

N-[4-tert-Butyl-2-(3-{4-[4-(1-methyl-piperidin-4-yloxy)-phenyl]-naphthalen-1-yl}-ureido)-phenyl]-acetamide

and the pharmaceutically acceptable derivatives thereof.

In yet another embodiment of the invention, there is provided thefollowing compounds of the formula(II):

1-(2-tert-Butyl-5-methyl-pyridin-4-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;

1-(3-Methyl-naphthalen-2-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;

1-(3-tert-Butyl-phenyl)-3-[4-(4-morpholin-4-ylmethyl-phenyl)-naphthalen-1-yl]-urea;

1-(3-tert-Butyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;

1-(4-Methyl-biphenyl-3-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;

1-(4-tert-Butyl-biphenyl-2-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;

1-(5-Chloro-2,4-dimethoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;

1-(5-Isopropyl-2-methyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;

1-(5-sec-Butyl-2-methoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;

1-(5-tert-Butyl-2-methoxy-3-propyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;

1-(5-tert-Butyl-2-methoxymethyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;

1-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(2-morpholin-4-ylmethyl-pyrimidin-5-yl)-naphthalen-1-yl]-urea;

1-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(4-thiomorpholin-4-ylmethyl-phenyl)-naphthalen-1-yl]-urea;

1-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;

1-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-phenyl)-naphthalen-1-yl]-urea;

1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[4-(tetrahydro-pyran-4-ylamino)-phenyl]-naphthalen-1-yl}-urea;1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(4-methyl-piperazin-1-ylmethyl)-pyridin-3-yl]-naphthalen-1-yl}-urea;

1-(5-tert-Butyl-2-methyl-phenyl)-3-(4-{6-[(3-methoxy-propyl)-methyl-amino]-pyridin-3-yl}-naphthalen-1-yl)-urea;

1-(5-tert-Butyl-2-methyl-phenyl)-3-[4-(4-morpholin-4-ylmethyl-imidazol-1-yl)-naphthalen-1-yl]-urea;

1-(5-tert-Butyl-2-methyl-phenyl)-3-[4-(4-morpholin-4-ylmethyl-phenyl)-naphthalen-1-yl]-urea;

1-(5-tert-Butyl-2-methyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;

1-(5-tert-Butyl-2-methyl-phenyl)-3-{4-[6-(3-methoxy-propylamino)-pyridin-3-yl]-naphthalen-1-yl}-urea;

1-(5-tert-Butyl-2-methyl-pyridin-3-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;

1-(5-tert-Butyl-2-morpholin-4-yl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;

1-(6-tert-Butyl-2-chloro-3-methyl-pyridin-4-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;

1-(6-tert-Butyl-2-chloro-3-methyl-pyridin-4-yl)-3-[4-(6-thiomorpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;

1-[2-Methoxy-5-(1-methyl-cyclopropyl)-phenyl]-3-[4-(2-morpholin-4-ylmethyl-pyrimidin-5-yl)-naphthalen-1-yl]-urea;

1-[4-(6-Morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-3-(3-trifluoromethyl-phenyl)-urea;

1-[4-(6-Morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-3-(4-trifluoromethoxy-phenyl)-urea;

1-[5-(1,1-Dimethyl-propyl)-2-methoxy-phenyl]-3-[4-(4-thiomorpholin-4-ylmethyl-phenyl)-naphthalen-1-yl]-urea;

1-[5-(1,1-Dimethyl-propyl)-2-methoxy-phenyl]-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;

1-[5-(1-Cyano-cyclopropyl)-2-methoxy-phenyl]-3-[4-(2-morpholin-4-ylmethyl-pyrimidin-5-yl)-naphthalen-1-yl]-urea;

1-[5-tert-Butyl-2-(1H-pyrazol-4-yl)-phenyl]-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;

1-[5-tert-Butyl-2-(2-methyl-pyrimidin-5-yl)-phenyl]-3-[4-(5-pyridin-4-ylmethyl-pyridin-2-yl)-naphthalen-1-yl]-urea;

1-[5-tert-Butyl-2-(2-methyl-pyrimidin-5-yl)-phenyl]-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;

1-[5-tert-Butyl-2-(3-hydroxy-propyl)-phenyl]-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;

1-[5-tert-Butyl-2-(3-morpholin-4-yl-3-oxo-propyl)-phenyl]-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;

1-[5-tert-Butyl-2-(morpholine-4-carbonyl)-phenyl]-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;

2-[4-tert-Butyl-2-(3-{4-[6-(2,6-dimethyl-morpholin-4-ylmethyl)-pyridin-3-yl]-naphthalen-1-yl}-ureido)-phenoxy]-acetamide;

3-{4-[3-(5-tert-Butyl-2-methoxy-phenyl)-ureido]-naphthalen-1-yl}-benzamide;

4-tert-Butyl-2-{3-[4-(2-chloro-4-morpholin-4-ylmethyl-phenyl)-naphthalen-1-yl]-ureido}-benzamide;

and the pharmaceutically acceptable derivatives thereof.

In yet a further another embodiment of the invention there is providedthe following compounds of the formula(II):

1-(2-tert-Butyl-5-methyl-pyridin-4-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;

1-(3-tert-Butyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;

1-(4-Methyl-biphenyl-3-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;

1-(4-tert-Butyl-biphenyl-2-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;

1-(5-Isopropyl-2-methyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;

1-(5-sec-Butyl-2-methoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;

1-(5-tert-Butyl-2-methoxymethyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;

1-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;

1-(5-tert-Butyl-2-methyl-phenyl)-3-(4-{6-[(3-methoxy-propyl)-methyl-amino]-pyridin-3-yl}-naphthalen-1-yl)-urea;

1-(5-tert-Butyl-2-methyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;

1-(5-tert-Butyl-2-methyl-pyridin-3-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;

1-[5-(1,1-Dimethyl-propyl)-2-methoxy-phenyl]-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;

1-[5-tert-Butyl-2-(1H-pyrazol-4-yl)-phenyl]-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl-naphthalen-1-yl]-urea;

1-[5-tert-Butyl-2-(2-methyl-pyrimidin-5-yl)-phenyl]-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;

1-[5-tert-Butyl-2-(3-hydroxy-propyl)-phenyl]-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;

1-[5-tert-Butyl-2-(morpholine-4-carbonyl)-phenyl]-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;

N-(5-tert-Butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-ureido}-phenyl)-acetamide

and the pharmaceutically acceptable derivatives thereof.

In yet still another generic aspect of the invention, there is providedcompounds of the formula(III):

wherein:

E is carbon or a heteroatom group chosen from —O—, —NH—and —S—;

G is:

an aromatic C₆₋₁₀ carbocycle or a nonaromatic C₃₋₁₀carbocycle saturatedor unsaturated;

a 6-14 membered monocyclic, bicyclic or tricyclic heteroaryl containing1 or more heteroatoms chosen from O, N and S;

a 6-8 membered monocyclic heterocycle containing one or more heteroatomschosen from O, N and S;

or

an 8-11 membered bicyclic heterocycle, containing one or moreheteroatoms chosen from O, N and S;

wherein G is optionally substituted by one or more R₁, R₂ or R₃;

Ar is:

phenyl, naphthyl, quinolinyl, isoquinolinyl, tetrahydronaphthyl,tetrahydroquinolinyl, tetrahydroisoquinolinyl, benzimidazolyl,benzofuranyl, dihydrobenzofuranyl, indolinyl, benzothienyl,dihydrobenzothienyl, indanyl, indenyl or indolyl each being optionallysubstituted by one or more R₄ or R₅;

X is:

a C₅₋₈ cycloalkyl or cycloalkenyl optionally substituted with one to twooxo groups or one to three C₁₋₄ alkyl, C₁₋₄ alkoxy or C₁₋₄ alkylaminochains each being branched or unbranched;

aryl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, pyridinyl,pyrimidinyl, pyridinonyl, dihydropyridinonyl, maleimidyl,dihydromaleimidyl, piperdinyl, benzimidazole, 3H-imidazo[4,5-b]pyridine,piperazinyl, pyridazinyl or pyrazinyl; each being optionallyindependently substituted with one to three C₁₋₄ alkyl, C₁₋₄alkoxy,hydroxy, nitrile, amino, mono- or di-(C₁₋₃ alkyl)amino, mono- ordi-(C₁₋₃ alkylamino)carbonyl, NH₂C(O), C₁₋₆ alkyl-S(O)_(m) or halogen;

Y is:

a bond or a C₁₋₄ saturated or unsaturated branched or unbranched carbonchain optionally partially or fully halogenated, wherein one or more Catoms are optionally replaced by O, N, or S(O)_(m) and wherein Y isoptionally independently substituted with one to two oxo groups,nitrile, phenyl or one or more C₁₋₄ alkyl optionally substituted by oneor more halogen atoms;

Z is:

aryl, heteroaryl selected from pyridinyl, piperazinyl, pyrimidinyl,pyridazinyl, pyrazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl,furanyl, thienyl and pyranyl, heterocycle selected fromtetrahydropyrimidonyl, cyclohexanonyl, cyclohexanolyl, 2-oxa- or2-thia-5-aza-bicyclo[2.2.1]heptanyl, pentamethylene sulfidyl,pentamethylene sulfoxidyl, pentamethylene sulfonyl, tetramethylenesulfidyl, tetramethylene sulfoxidyl or tetramethylene sulfonyl,tetrahydropyranyl, tetrahydrofuranyl, 1,3-dioxolanonyl, 1, 3-dioxanonyl,1,4-dioxanyl, morpholino, thiomorpholino, thiomorpholino sulfoxidyl,thiomorpholino sulfonyl, piperidinyl, piperidinonyl, pyrrolidinyl anddioxolanyl, each of the aforementioned Z are optionally substituted withone to three halogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₃ alkoxy-C₁₋₃ alkyl,C₁₋₆ alkoxycarbonyl, aroyl, C₁₋₃acyl, oxo, hydroxy, pyridinyl-C₁₋₃alkyl, imidazolyl-C₁₋₃ alkyl, tetrahydrofuranyl-C₁₋₃ alkyl, nitrile-C₁₋₃alkyl, nitrile, carboxy, phenyl wherein the phenyl ring is optionallysubstituted with one to two halogen, C₁₋₆ alkoxy, hydroxy or mono- ordi-(C₁₋₃ alkyl)amino, C₁₋₆ alkyl-S(O)_(m), or phenyl-S(O)_(m) whereinthe phenyl ring is optionally substituted with one to two halogen, C₁₋₆alkoxy, hydroxy, halogen or mono- or di-(C₁₋₃ alkyl)amino; or Z isoptionally substituted with one to three amino or amino-C₁₋₃ alkylwherein the N atom is optionally independently mono- or di-substitutedby aminoC₁₋₆alkyl, C₁₋₃alkyl, arylC₀₋₃alkyl, C₁₋₅ alkoxyC₁₋₃ alkyl, C₁₋₅alkoxy, aroyl, C₁₋₃acyl, C₁₋₃alkyl-S(O)_(m)— or arylC₀₋₃alkyl-S(O)_(m)—each of the aforementioned alkyl and aryl attached to the amino group isoptionally substituted with one to two halogen, C₁₋₆ alkyl or C₁₋₆alkoxy; or Z is optionally substituted with one to three aryl,heterocycle or heteroaryl as hereinabove described in this paragrapheach in turn is optionally substituted by halogen, C₁₋₆ alkyl or C₁₋₆alkoxy;

or Z is hydroxy, halogen, nitrile, amino wherein the N atom isoptionally independently mono- or di-substituted by C₁₋₃acyl, C₁₋₆alkylor C₁₋₃alkoxyC₁₋₃alkyl, C₁₋₆alkyl branched or unbranched, C₁₋₆alkoxy,C₁₋₃acylamino, nitrileC₁₋₄alkyl, C₁₋₆ alkyl-S(O)_(m), andphenyl-S(O)_(m), wherein the phenyl ring is optionally substituted withone to two halogen, C₁₋₆ alkoxy, hydroxy or mono- or di-(C₁₋₃alkyl)amino;

each R₁ is independently:

C₁₋₁₀ alkyl branched or unbranched optionally partially or fullyhalogenated, wherein one or more C atoms are optionally independentlyreplaced by O, N or S(O)_(m), and wherein said C₁₋₁₀ alkyl is optionallysubstituted with one to three C₃₋₁₀ cycloalkyl, hydroxy, oxo, phenyl,naphthyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl,pyrrolidinyl, imidazolyl, pyrazolyl, thienyl, furyl, dioxolanyl,isoxazolyl or isothiazolyl; each of the aforementioned being optionallysubstituted with one to five groups selected from halogen, C₁₋₆ alkylwhich is optionally partially or fully halogenated, C₃₋₈ cycloalkanyl,C₅₋₈ cycloalkenyl, hydroxy, nitrile, C₁₋₃ alkoxy which is optionallypartially or fully halogenated or NH₂C(O), mono- or di(C₁₋₃alkyl)amino,and mono- or di(C₁₋₃alkyl)aminocarbonyl;

or R, is

cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, orcycloheptyloxy each being optionally partially or fully halogenated andoptionally substituted with one to three C₁₋₃ alkyl groups optionallypartially or fully halogenated, nitrile, hydroxyC₁₋₃alkyl or aryl; or ananalog of such cycloalkyl group wherein one to three ring methylenegroups are independently replaced by O, S(O)_(m), CHOH,>C═O,>C═S or NH;

phenyloxy or benzyloxy each being optionally partially or fullyhalogenated and optionally substituted with one to three C₁₋₃ alkylgroups optionally partially or fully halogenated, nitrile,hydroxyC₁₋₃alkyl or aryl; or an analog of such cycloaryl group whereinone to two ring methyne groups are independently replaced by N;

cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,bicyclopentanyl, bicyclohexanyl or bicycloheptanyl, each beingoptionally partially or fully halogenated and optionally substitutedwith one to three C₁₋₃ alkyl optionally partially or fully halogenated,nitrile, hydroxyC₁₋₃alkyl or aryl; or an analog of such cycloalkyl groupwherein one to three ring methylene groups are independently replaced byO, S(O)_(m), CHOH,>C═O,>C═S or NH;

C₃₋₁₀ branched or unbranced alkenyl each being optionally partially orfully halogenated, and optionally substituted with one to three C₁₋₅branched or unbranched alkyl, phenyl, naphthyl, pyridinyl, pyrimidinyl,pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl,isoxazolyl or isothiazolyl, each of the aforementioned being substitutedwith one to five halogen, C₁₋₆ alkyl which is optionally partially orfully halogenated, cyclopropanyl, cyclobutanyl, cyclopentanyl,cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl andbicycloheptanyl, hydroxy, nitrile, C₁₋₃ alkyloxy which is optionallypartially or fully halogenated, NH₂C(O), mono- or di(C₁₋₃alkyl)aminocarbonyl; the C₃₋₁₀ branched or unbranced alkenyl beingoptionally interrupted by one or more heteroatoms chosen from O, N andS(O)_(m);

cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl,cycloheptadienyl, bicyclohexenyl or bicycloheptenyl, wherein suchcycloalkenyl group is optionally substituted with one to three C₁₋₃alkyl groups;

oxo, nitrile, halogen;

silyl containing three C₁₋₄ alkyl groups optionally partially or fullyhalogenated; or

C₃₋₆ alkynyl branched or unbranched carbon chain optionally partially orfully halogenated, wherein one or more methylene groups are optionallyreplaced by O, NH or S(O)_(m) and wherein said alkynyl group isoptionally independently substituted with one to two oxo groups,hydroxy, pyrroldinyl, pyrrolyl, tetrahydropyranyl, one or more C₁₋₄alkyl optionally substituted by one or more halogen atoms, nitrile,morpholino, piperidinyl, piperazinyl, imidazolyl, phenyl, pyridinyl,tetrazolyl, or mono- or di(C₁₋₃alkyl)amino optionally substituted by oneor more halogen atoms;

each R₂, R_(4,) and R₅ is

a C₁₋₆ branched or unbranched alkyl optionally partially or fullyhalogenated, C₁₋₆acyl, aroyl, C₁₋₄ branched or unbranched alkoxy, eachbeing optionally partially or fully halogenated, halogen,methoxycarbonyl, C₁₋₃ alkyl-S(O)_(m) optionally partially or fullyhalogenated, or phenyl-S(O)_(m);

OR_(6,) C₁₋₆ alkoxy, hydroxy, nitrile, nitro, halogen;

or amino-S(O)_(m)— wherein the N atom is optionally independently mono-or di-substituted by C₁₋₆alkyl or arylC₀₋₃alkyl, or amino wherein the Natom is optionally independently mono- or di-substituted by C₁₋₃alkyl,arylC₀₋₃alkyl, C₁₋₆acyl, C₁₋₆alkyl-S(O)_(m)— or arylC₀₋₃alkyl-S(O)_(m)—, each of the aforementioned alkyl and aryl in thissubparagraph are optionally partially or fully halogenated andoptionally substituted with one to two C₁₋₆ alkyl or C₁₋₆ alkoxy;

each R₃ is independently:

phenyl, naphthyl, morpholino, pyridinyl, pyrimidinyl, pyrazinyl,pyridazinyl, pyrrolyl, pyrrolidinyl, imidazolyl, pyrazolyl, thiazolyl,oxazoyl, [1,3,4]oxadiazol, triazolyl, tetrazolyl, thienyl, furyl,tetrahydrofuryl, isoxazolyl, isothiazolyl, quinolinyl, isoquinolinyl,indolyl, benzimidazolyl, benzofuranyl, benzoxazolyl, benzisoxazolyl,benzpyrazolyl, benzothiofuranyl, cinnolinyl, pterindinyl, phthalazinyl,naphthypyridinyl, quinoxalinyl, quinazolinyl, purinyl or indazolyl, eachof the aforementioned is optionally substituted with one to threephenyl, naphthyl, heterocycle or heteroaryl as hereinabove described inthis paragraph, C₁₋₆ branched or unbranched alkyl which is optionallypartially or fully halogenated, cyclopropanyl, cyclobutanyl,cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl,bicyclohexanyl, bicycloheptanyl, phenyl C₁₋₅ alkyl, naphthyl C₁₋₅ alkyl,halogen, hydroxy, oxo, nitrile, C₁₋₃ alkoxy optionally partially orfully halogenated, phenyloxy, naphthyloxy, heteroaryloxy orheterocyclicoxy wherein the heterocyclic or heteroaryl moiety is ashereinabove described in this paragraph, nitro, amino, mono- ordi-(C₁₋₃alky)lamino, phenylamino, naphthylamino, heteroaryl orheterocyclic amino wherein the heteroaryl heterocyclic moiety is ashereinabove described in this paragraph, NH₂C(O), a mono- ordi-(C₁₋₃alkyl) aminocarbonyl, C₁₋₅ alkyl-C(O)—C₁₋₄ alkyl, amino-C₁₋₅alkyl, mono- or di-(C₁₋₅alkyl)amino, mono- or di-(C₁₋₃alkyl)amino-C₁₋₅alkyl, amino-S(O)₂, di-(C₁₋₃alkyl)amino-S(O)₂, R₇—C₁₋₅ alkyl, R₈—C₁₋₅alkoxy, R₉—C(O)—C₁₋₅ alkyl, R₁₀—C₁₋₅ alkyl(R₁₁)N, carboxy-mono- ordi-(C₁₋₅alkyl)-amino;

a fused aryl selected from benzocyclobutanyl, indanyl, indenyl,dihydronaphthyl, tetrahydronaphthyl, benzocycloheptanyl andbenzocycloheptenyl, or a fused heteroaryl selected fromcyclopentenopyridinyl, cyclohexanopyridinyl, cyclopentanopyrimidinyl,cyclohexanopyrimidinyl, cyclopentanopyrazinyl, cyclohexanopyrazinyl,cyclopentanopyridazinyl, cyclohexanopyridazinyl, cyclopentanoquinolinyl,cyclohexanoquinolinyl, cyclopentanoisoquinolinyl,cyclohexanoisoquinolinyl, cyclopentanoindolyl, cyclohexanoindolyl,cyclopentanobenzimidazolyl, cyclohexanobenzimidazolyl,cyclopentanobenzoxazolyl, cyclohexanobenzoxazolyl,cyclopentanoimidazolyl, cyclohexanoimidazolyl, cyclopentanothienyl andcyclohexanothienyl; wherein the fused aryl or fused heteroaryl ring isindependently substituted with zero to three phenyl, naphthyl,pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl,pyrazolyl, thienyl, furyl, isoxazolyl, isothiazolyl, C₁₋₆ alkyl which isoptionally partially or fully halogenated, halogen, nitrile, C₁₋₃alkyloxy which is optionally partially or fully halogenated, phenyloxy,naphthyloxy, heteroaryloxy or heterocyclicoxy wherein the heteroaryl orheterocyclic moiety is as hereinabove described in this paragraph,nitro, amino, mono- or di-(C₁₋₃alkyl)amino, phenylamino, naphthylamino,heteroaryl or heterocyclic amino wherein the heteroaryl or heterocyclicmoiety is as hereinabove described in this paragraph, NH₂C(O), mono- ordi-(C₁₋₃alkyl)aminocarbonyl, C₁₋₄ alkyl-OC(O), C₁₋₅ alkyl-C(O)—C₁₋₄alkyl, amino-C₁₋₅ alkyl, mono- or di-(C₁₋₃)alkylamino-C₁₋₅ alkyl,R₁₂—C₁₋₅ alkyl, R₁₃—C₁₋₅ alkoxy, R₁₄—C(O)—C(O)—C₁₋₅ alkyl or R₁₅—C₁₋₅alkyl(R₁₆)N;

cyclopropanyl, cyclobutanyl, cyclopentanyl, cyclohexanyl, cycloheptanyl,bicyclopentanyl, bicyclohexanyl or bicycloheptanyl, each beingoptionally be partially or fully halogenated and optionally substitutedwith one to three C₁₋₃ alkyl groups, or an analog of such cycloalkylgroup wherein one to three ring methylene groups are independentlyreplaced by O, S, CHOH,>C═O,>C═S or NH;

cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl,cycloheptadienyl, bicyclohexenyl or bicycloheptenyl, each optionallysubstituted with one to three C₁₋₃ alkyl groups;

C₁₋₄ alkyl-phenyl-C(O)—C₁₋₄ alkyl-, C₁₋₄ alkyl-C(O)—C₁₋₄ alkyl- or C₁₋₄alkyl-phenyl-S(O)_(m)—C₁₋₄ alkyl-;

C₁₋₆ alkyl or C₁₋₆ branched or unbranched alkoxy each of which isoptionally partially or fully halogenated or optionally substituted withR₁₇;

OR₁₈ or C₁₋₆ alkyl optionally substituted with OR₁₈;

amino or mono- or di-(C₁₋₅alkyl)amino optionally substituted with R₁₉;

R₂₀C(O)N(R₂₁)—, R₂₂O— or R₂₃R₂₄NC(O)—; R₂₆(CH₂)_(m)C(O)N(R₂₁)—,R₂₃R₂₄NC(O)—C₁₋₃alkoxy or R₂₆C(O)(CH₂)_(m)N(R₂₁)—;

C₂₋₆alkenyl substituted by R₂₃R₂₄NC(O)—;

C₂₋₆ alkynyl branched or unbranched carbon chain, optionally partiallyor fully halogenated, wherein one or more methylene groups areoptionally replaced by O, NH, S(O)_(m) and wherein said alkynyl group isoptionally independently substituted with one to two oxo groups,pyrroldinyl, pyrrolyl, morpholino, piperidinyl, piperazinyl, imidazolyl,phenyl, pyridinyl, tetrazolyl one or more C₁₋₄ alkyl optionallysubstituted by one or more halogen atoms, nitrile, morpholino,piperidinyl, piperazinyl, imidazolyl, phenyl, pyridinyl, tetrazolyl, ormono- or di(C₁₋₄ alkyl)amino optionally substituted by one or morehalogen atoms;

C₁₋₆acyl or aroyl;

R₆ is a:

C₁₋₄ alkyl optionally partially or fully halogenated and optionallysubstituted with R₂₆;

each R₇, R₈, R₉, R₁₀, R₁₂, R₁₃, R₁₄, R₁₅, R₁₇, R₁₉, R₂₅ and R₂₆ isindependently:

nitrile, phenyl, morpholino, piperidinyl, piperazinyl, imidazolyl,pyridinyl, tetrazolyl, amino or mono- or di-(C₁₋₄alkyl)amino optionallypartially or fully halogenated;

each R₁₁ and R₁₆ is independently:

hydrogen or C₁₋₄ alkyl optionally partially or fully halogenated;

R₁₈ is independently:

hydrogen or a C₁₋₄ alkyl optionally independently substituted with oxoor R₂₅;

R₂₀ is independently:

C₁₋₁₀ alkyl optionally partially or fully halogenated, phenyl, orpyridinyl;

R₂₁ is independently:

hydrogen or C₁₋₃ alkyl optionally partially or fully halogenated;

each R₂₂, R₂₃ and R₂₄ is independently:

hydrogen, C₁₋₆ alkyl optionally partially or fully halogenated, saidC₁₋₆ alkyl is optionally interrupted by one or more O, N or S, said C₁₋₆alkyl also being independently optionally substituted by mono- ordi-(C₁₋₃alkyl)aminocarbonyl, phenyl, pyridinyl, amino or mono-ordi-(C₁₋₄alkyl)amino each of which is optionally partially or fullyhalogenated and optionally substituted with mono- ordi-(C₁₋₃alkyl)amino;

or R₂₃ and R₂₄ taken together optionally form a heterocyclic orheteroaryl ring;

m=0, 1 or 2;

W is O or S and

pharmaceutically acceptable derivatives thereof.

In another embodiment of the invention there is provided compounds ofthe formula(III) as described above and wherein:

E is —CH₂—, —NH—or —O—;

W is O;

and

G is:

phenyl, naphthyl, benzocyclobutanyl, dihydronaphthyl,tetrahydronaphthyl, benzocycloheptanyl, benzocycloheptenyl, indanyl,indenyl; pyridinyl, pyridonyl, quinolinyl, dihydroquinolinyl,tetrahydroquinoyl, isoquinolinyl, tetrahydroisoquinoyl, pyridazinyl,pyrimidinyl, pyrazinyl, benzimidazolyl, benzthiazolyl, benzooxazolyl,benzofuranyl, benzothiophenyl, benzpyrazolyl, dihydrobenzofuranyl,dibenzofuranyl, dihydrobenzothiophenyl, benzooxazolonyl,benzo[1,4]oxazin-3-onyl, benzodioxolyl, benzo[1,3]dioxol-2-onyl,benzofuran-3-onyl, tetrahydrobenzopyranyl, indolyl,2,3-dihydro-1H-indolyl, indolinyl, indolonyl, indolinonyl, phthalimidyl,chromoyl;

oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl,piperidinyl, piperazinyl, morpholino, tetrahydropyranyl, dioxanyl,tetramethylene sulfonyl, tetramethylene sulfoxidyl, oxazolinyl,3,4-dihydro-2H-benzo[1,4]oxazinyl, thiazolinyl, imidazolinyl,tertrahydropyridinyl, homopiperidinyl, pyrrolinyl,tetrahydropyrimidinyl, decahydroquinolinyl, decahydroisoquinolinyl,thiomorpholino, thiazolidinyl, dihydrooxazinyl, dihydropyranyl,oxocanyl, heptacanyl, thioxanyl or dithianyl; wherein G is optionallysubstituted by one or more R₁, R₂ or R₃.

In yet another embodiment there are provided compounds of theformula(III) as described immediately above and wherein:

E is —NH—;

G is phenyl, pyridinyl, pyridonyl, naphthyl, quinolinyl, isoquinolinyl,pyrazinyl, benzimidazolyl, benzooxazolyl, benzooxazolonyl, benzofuranyl,benzothiophenyl, benzpyrazolyl, dihydrobenzofuranyl,dihydrobenzothiophenyl, 3,4-dihydro-2H-benzo[1,4]oxazinyl, indanyl,indenyl, indolyl, indolinyl, indolonyl, 2,3-dihydro-1H-indolyl orindolinonyl, wherein G is optionally substituted by one or more R₁, R₂or R₃;

Ar is:

naphthyl, quinolinyl, isoquinolinyl, tetrahydronaphthyl,tetrahydroquinolinyl, tetrahydroisoquinolinyl, indanyl, indenyl orindolyl each being optionally substituted by one or more R₄ or R₅groups;

X is:

phenyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, pyridinyl,pyrimidinyl, pyridinonyl, dihydropyridinonyl, maleimidyl,dihydromaleimidyl, piperdinyl, piperazinyl, pyridazinyl or pyrazinyl;each being optionally independently substituted with one to three C₁₋₄alkyl, C₁₋₄alkoxy, hydroxy, nitrile, amino, mono- or di-(C₁₋₃alkyl)amino, mono- or di-(C₁₋₃ alkylamino)carbonyl, NH₂C(O), C₁₋₆alkyl-S(O)_(m) or halogen;

Y is:

a bond or

a C₁₋₄ saturated or unsaturated carbon chain wherein one or more of theC atoms is optionally replaced by O, N, or S(O)_(m) and wherein Y isoptionally independently substituted with one to two oxo groups,nitrile, phenyl or one or more C₁₋₄ alkyl optionally substituted by oneor more halogen atoms;

Z is:

phenyl, heteroaryl selected from pyridinyl, piperazinyl, pyrimidinyl,pyridazinyl, pyrazinyl, imidazolyl, furanyl, thienyl and pyranyl,heterocycle selected from 2-oxa-5-aza-bicyclo[2.2.1]heptanyl,tetrahydropyrimidonyl, pentamethylene sulfidyl, pentamethylenesulfoxidyl, pentamethylene sulfonyl, tetramethylene sulfidyl,tetramethylene sulfoxidyl tetramethylene sulfonyl, tetrahydropyranyl,tetrahydrofaranyl, 1,3-dioxolanonyl, 1,3-dioxanonyl, 1,4-dioxanyl,morpholino, thiomorpholino, thiomorpholino sulfoxidyl, piperidinyl,piperidinonyl, dihydrothiazolyl, dihydrothiazolyl sulfoxidyl,pyrrolidinyl and dioxolanyl which are optionally substituted with one tothree nitrile, C₁₋₃ alkyl, C₁₋₃ alkoxy, amino, mono- or di-(C₁₋₃alkyl)amino, CONH₂ or OH; or Z is optionally substituted by phenyl,heterocycle or heteroaryl as hereinabove described in this paragrapheach in turn is optionally substituted by halogen, C₁₋₃ alkyl or C₁₋₃alkoxy;

or Z is nitrile, nitrileC₁₋₃ alkyl, C₁₋₆ alkyl-S(O)_(m), halogen,hydroxy, C₁₋₃ alkyl, C₁₋₃ acylamino, C₁₋₄ alkoxy, amino, mono- ordi-(C₁₋₃ alkyl)aminocarbonyl, or amino mono or di-substituted byaminoC₁₋₆ alkyl or C₁₋₃alkoxyC₁₋₃alkyl;

each R₁ is independently:

C₁₋₆ alkyl branched or unbranched optionally partially or fullyhalogenated, wherein one or more C atoms are optionally independentlyreplaced by O, N or S(O)_(m), and wherein said C₁₋₆ alkyl is optionallysubstituted with one to three C₃₋₆cycloalkyl, oxo, phenyl, dioxolanyl,pyrrolidinyl, furyl, isoxazolyl or isothiazolyl; each of theaforementioned being optionally substituted with one to three groupsselected from halogen, C₁₋₃ alkyl which is optionally partially or fullyhalogenated, hydroxy, nitrile and C₁₋₃alkoxy which is optionallypartially or fully halogenated;

cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, bicyclopentanyl orbicyclohexanyl, each being optionally partially or fully halogenated andoptionally substituted with one to three C₁₋₃ alkyl groups optionallypartially or fully halogenated, nitrile, hydroxyC₁₋₃alkyl or phenyl; oran analog of such cycloalkyl group wherein one to three ring methylenegroups are independently replaced by O, S, CHOH,>C═O,>C═S or NH;

oxo;

C₃₋₆ alkynyl branched or unbranched carbon chain optionally partially orfully halogenated, wherein one or more methylene groups are optionallyreplaced by O, NH or S(O)_(m) and wherein said alkynyl group isoptionally independently substituted with one to two oxo groups,hydroxy, pyrroldinyl, pyrrolyl, tetrahydropyranyl, C₁₋₄ alkyl optionallysubstituted by one or more halogen atoms, nitrile, morpholino,piperidinyl, piperazinyl, imidazolyl, phenyl, pyridinyl, tetrazolyl, ormono- or di(C₁₋₃alkyl)amino optionally substituted by one or morehalogen atoms;

or

silyl containing three C₁₋₄ alkyl groups optionally partially or fullyhalogenated;

R₂ is independently:

a C₁₋₅ branched or unbranched alkyl optionally partially or fullyhalogenated, acetyl, aroyl, C₁₋₄ branched or unbranched alkoxy, eachbeing optionally partially or fully halogenated, halogen,methoxycarbonyl, C₁₋₂ alkyl-S(O)_(m) optionally partially or fullyhalogenated, or phenyl-S(O)_(m);

C₁₋₃ alkoxy, hydroxy, nitrile, nitro, halogen;

or amino-S(O)_(m)— wherein the N atom is optionally independently mono-or di-substituted by C₁₋₃alkyl or arylC₀₋₃alkyl, or amino wherein the Natom is optionally independently mono- or di-substituted by C₁₋₃alkyl,arylC₀₋₃alkyl, C₁₋₃acyl, C₁₋₄alkyl-S(O)_(m)— or arylC₀₋₃alkyl-S(O)_(m)—, each of the aforementioned alkyl and aryl in thissubparagraph are optionally partially or fully halogenated andoptionally substituted with one to two C₁₋₃ alkyl or C₁₋₃ alkoxy;

R₃ is independently:

phenyl, morpholino, pyridinyl, pyrimidinyl, pyrazinyl, pyrrolyl,pyrrolidinyl, imidazolyl, [1,3,4]oxadiazol, pyrazolyl, each isoptionally substituted with one to three phenyl, naphthyl, heterocycleor heteroaryl as hereinabove described in this paragraph, C₁₋₆ alkylwhich is optionally partially or fully halogenated, cyclopropanyl,cyclobutanyl, cyclopentanyl, cyclohexanyl, cycloheptanyl,bicyclopentanyl, bicyclohexanyl, bicycloheptanyl, phenyl C₁₋₅ alkyl,naphthyl C₁₋₅ alkyl, halogen, oxo, hydroxy, nitrile, C₁₋₃ alkoxyoptionally partially or fully halogenated, phenyloxy, naphthyloxy,heteroaryloxy or heterocyclicoxy wherein the heteroaryl or heterocyclicmoiety is as hereinabove described in this paragraph, nitro, amino,mono- or di-(C₁₋₃alkyl)amino, phenylamino, naphthylamino, heteroaryl orheterocyclic amino wherein the heteroaryl or heterocyclic moiety is ashereinabove described in this paragraph, NH₂C(O), a mono- ordi-(C₁₋₃alkyl)aminocarbonyl, C₁₋₅ alkyl-C(O)—C₁₋₄ alkyl, mono- ordi-(C₁₋₃alkyl)amino, mono- or di-(C₁₋₃)alkylamino-C₁₋₅ alkyl, mono- ordi-(C₁₋₃alkyl)amino-S(O)₂, R₇—C₁₋₅ alkyl, R₈—C₁₋₅ alkoxy, R₉—C(O)—C₁₋₅alkyl, R₁₀ —C₁₋₅ alkyl(R₁₁)N, carboxy-mono- or di-(C₁₋₅)-alkyl-amino;

C₁₋₃ alkyl or C₁₋₄ alkoxy each being optionally partially or fullyhalogenated or optionally substituted with R₁₇;

OR₁₈ or C₁₋₆ alkyl optionally substituted with OR₁₈;

amino or mono- or di-(C₁₋₅ alkyl)amino optionally substituted with R₁₉;R₂₀C(O)N(R₂₁)—, R₂₂O—; R₂₃R₂₄NC(O)—; R₂₆CH₂C(O)N(R₂₁)—,R₂₃R₂₄NC(O)—C₁₋₂alkoxy or R₂₆C(O)CH₂N(R₂₁)—;

C₂₋₄alkenyl substituted by R₂₃R₂₄NC(O)—; or

C₂₋₄ alkynyl branched or unbranched carbon chain optionally partially orfully halogenated wherein one of the methylene groups is optionallyreplaced by O, and optionally independently substituted with one to twooxo groups, pyrroldinyl, pyrrolyl, morpholino, piperidinyl, piperazinyl,imidazolyl, phenyl, pyridinyl, tetrazolyl or one or more C₁₋₄ alkyloptionally substituted by one or more halogen atoms;

C₁₋₃acyl; and

R₂₃ and R₂₄ taken together optionally form imidazolyl, piperidinyl,morpholino, piperazinyl or a pyridinyl ring.

In yet still another embodiment of the invention there is providedcompounds of the formula(III) as described immediately above andwherein:

G is phenyl, pyridinyl, pyridonyl, naphthyl, quinolinyl, isoquinolinyl,pyrazinyl, 3,4-dihydro-2H-benzo[1,4]oxazinyl, benzothiophenyl,dihydrobenzofuranyl, dihydrobenzothiophenyl, benzooxazolyl, indanyl,indolyl, indolinyl, indolonyl or indolinonyl, wherein G is optionallysubstituted by one or more R₁, R₂ or R₃;

Ar is naphthyl;

X is

phenyl, imidazolyl, pyridinyl, pyrimidinyl, piperdinyl, piperazinyl,pyridazinyl or pyrazinyl each being optionally independently substitutedwith one to three C₁₋₄ alkyl, C₁₋₄alkoxy, hydroxy, nitrile, amino, mono-or di-(C₁₋₃ alkyl)amino, mono- or di-(C₁₋₃ alkylamino)carbonyl, NH₂C(O),C₁₋₆ alkyl-S(O)_(m) or halogen;

Y is:

a bond or a C₁₋₄ saturated carbon chain wherein one or more of the Catoms is optionally replaced by O, N or S and wherein Y is optionallyindependently substituted with nitrile or oxo;

Z is:

phenyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, imidazolyl,dihydrothiazolyl, dihydrothiazolyl sulfoxide, pyranyl, pyrrolidinyl,phenylpiperazinyl, tetrahydropyranyl, tetrahydrofuranyl, dioxolanyl,2-oxa-5-aza-bicyclo[2.2.1]heptanyl, morpholino, thiomorpholino,thiomorpholino sulfoxidyl, piperidinyl, piperidinonyl, piperazinyl ortetrahydropyrimidonyl each of which are optionally substituted with oneto two C₁₋₂ alkyl or C₁₋₂ alkoxy; or

Z is hydroxy, C₁₋₃ alkyl, C₁₋₃ alkoxy, C₁₋₃ acylamino, C₁₋₃alkylsulfonyl, nitrile C₁₋₃ alkyl or amino mono or di-substituted byC₁₋₃ alkoxyC₁₋₃ alkyl;

each R₁ is independently:

C₁₋₅ alkyl branched or unbranched optionally partially or fullyhalogenated, wherein one or more C atoms are optionally independentlyreplaced by O, N or S(O)_(m), and wherein said C₁₋₅ alkyl is optionallysubstituted with oxo, dioxolanyl, pyrrolidinyl, furyl or phenyl eachoptionally substituted with one to three halogen, C₁₋₃ alkyl which isoptionally partially or fully halogenated, hydroxy, nitrile andC₁₋₃alkoxy which is optionally partially or fully halogenated;

cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, bicyclopentanyl orbicyclohexanyl, each being optionally partially or fully halogenated andoptionally substituted with one to three C₁₋₃ alkyl groups optionallypartially or fully halogenated, nitrile, hydroxyC₁₋₃ alkyl or phenyl;and an analog of cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl,bicyclopentanyl or bicyclohexanyl wherein one ring methylene group isreplaced by O;

oxo;

C₂₋₄ alkynyl optionally partially or fully halogenated wherein one ormore methylene groups are optionally replaced by O, and optionallyindependently substituted with one to two oxo groups, hydroxy,pyrroldinyl, pyrrolyl, tetrahydropyranyl, C₁₋₄ alkyl optionallysubstituted by one or more halogen atoms, nitrile, morpholino,piperidinyl, piperazinyl, imidazolyl, phenyl, pyridinyl, tetrazolyl, ormono- or di(C₁₋₃ alkyl)amino optionally substituted by one or morehalogen atoms; or

silyl containing three C₁₋₂ alkyl groups optionally partially or fullyhalogenated;

each R₂ is independently:

a C₁₋₄ alkyl optionally partially or fully halogenated, C₁₋₄ alkoxyoptionally partially or fully halogenated, bromo, chloro, fluoro,methoxycarbonyl, methyl-S(O)_(m), ethyl-S(O)_(m) each optionallypartially or fully halogenated or phenyl-S(O)_(m);

or R₂ is mono- or di-C₁₋₃acylamino, amino-S(O)_(m) or S(O)_(m) aminowherein the N atom is mono- or di-substituted by C₁₋₃ alkyl or phenyl,nitrile, nitro or amino;

each R₃ is independently:

phenyl, morpholino, pyridinyl, pyrimidinyl, pyrrolidinyl,2,5-pyrrolidin-dionyl, imidazolyl, [1,3,4]oxadiazol, pyrazolyl, each ofthe aforementioned is optionally substituted with one to three C₁₋₃alkyl which is optionally partially or fully halogenated, halogen, oxo,hydroxy, nitrile and C₁₋₃ alkoxy optionally partially or fullyhalogenated;

C₁₋₃ alkyl or C₁₋₃ alkoxy optionally partially or fully halogenated oroptionally substituted with R₁₇;

OR₁₈ or C₁₋₃ alkyl optionally substituted with OR₁₈; amino or mono- ordi-(C₁₋₃ alkyl)amino optionally substituted with R₁₉;

R₂₀C(O)N(R₂₁)—, R₂₂O—; R₂₃R₂₄NC(O)—; R₂₆CH₂C(O)N(R₂₁)—, NH₂C(O)methoxyor R₂₆C(O)CH₂N(R₂₁)—;

C₂₋₄ alkenyl substituted by R₂₃R₂₄NC(O)—; or

C₂₋₄ alkynyl substituted with pyrroldinyl or pyrrolyl;

C₁₋₃acyl and

R₂₃ and R₂₄ taken together optionally form morpholino.

In yet a further embodiment of the invention there is provided compoundsof the formula(III) as described immediately above and wherein:

G is phenyl, pyridinyl, pyridonyl, 2-naphthyl, quinolinyl,isoquinolinyl, dihydrobenzofuranyl, indanyl, 5-indolyl,3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl, benzooxalolyl,2,3-dihydrobenzooxazol-7-yl, 2-oxo-2,3-dihydro-1H-indol-5-yl, indolinyl,indolonyl, or indolinonyl, wherein G is optionally substituted by one ormore R₁, R₂ or R₃;

Ar is 1-naphthyl;

X is:

phenyl, imidazolyl, pyridinyl, pyrimidinyl, piperdinyl, piperazinyl,pyridazinyl or pyrazinyl;

Y is:

a bond or —CH₂—, —CH₂CH₂—, —C(O)—, —O—, —S—, —NH—CH₂CH₂CH₂—, —N(CH₃)—,—CH₂(CN)CH₂—NH—CH₂ or —NH—;

Z is

morpholino, dioxolanyl, tetrahydrofuranyl, pyridinyl,2-oxa-5-aza-bicyclo[2.2.1]heptanyl, C₁₋₃alkoxyphenylpiperazinyl,hydroxy, C₁₋₃ alkyl, N,N-diC₁₋₃alkoxyC₁₋₃ alkylamino, C₁₋₃acylamino,C₁₋₃ alkylsulfonyl or nitrileC₁₋₃ alkyl;

each R₁ is independently:

C₁₋₅ alkyl optionally partially or fully halogenated wherein one or moreC atoms are optionally independently replaced by O or N, and whereinsaid C₁₋₅ alkyl is optionally substituted with oxo, dioxolanyl,pyrrolidinyl, furyl or phenyl optionally substituted by C₁₋₃alkoxy;

cyclopropyl, cyclopentanyl, cyclohexanyl and bicyclopentanyl optionallysubstituted with one to three methyl groups optionally partially orfully halogenated, nitrile, hydroxymethyl or phenyl; or2-tetrahydrofuranyl substituted by methyl; or

trimethyl silyl;

propynyl substituted hydroxy or tetrahydropyran-2-yloxy;

R₂ is

is mono- or di-C₁₋₃acylamino, amino-S(O)_(m) or S(O)_(m) amino whereinthe N atom is mono- or di-substituted by C₁₋₃ alkyl or phenyl, bromo,chloro, fluoro, nitrile, nitro, amino, methylsulfonyl optionallypartially or fully halogenated or phenylsulfonyl;

each R₃ is independently:

phenyl, morpholino, pyridinyl, pyrimidinyl, pyrrolidinyl,2,5-pyrrolidin-dionyl, imidazolyl, [1,3,4]oxadiazol or pyrazolyl, eachis optionally substituted with C₁₋₂ alkyl which is optionally partiallyor fully halogenated;

C₁₋₃ alkyl or C₁₋₃ alkoxy each being optionally partially or fullyhalogenated or optionally substituted with diethylamino;

OR₁₈ or C₁₋₃ alkyl optionally substituted with OR₁₈;

amino or mono- or di-(C₁₋₃ alkyl)amino optionally substituted with R₁₉;

CH₃C(O)NH—, R₂₂O—; R₂₃R₂₄NC(O)—; R₂₆CH₂C(O)N(R₂₁)—, NH₂C(O)methoxy orR₂₆C(O)CH₂N(R₂₁)—;

C₂₋₄alkenyl substituted by R₂₃R₂₄NC(O)—; or

C₂₋₄ alkynyl substituted with pyrroldinyl or pyrrolyl;

C₁₋₂acyl; and

R₂₃ and R₂₄ are H or R₂₃ and R₂₄ taken together optionally formmorpholino; and

R₂₆ is morpholino.

In yet still a further embodiment of the invention there are providedcompounds of the formula(III) as described immediately above andwherein:

G is

phenyl, pyridinyl, 5-indolyl,3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl, benzooxalolyl,2,3-dihydrobenzooxazol-7-yl, 2-oxo-2,3-dihydro-1H-indol-5-yl or2-naphthyl wherein G is optionally substituted by one or more R₁, R₂ orR₃;

X is:

imidazolyl, pyridinyl, pyrimidinyl or pyrazinyl;

Y is:

a bond, CH₂(CN)CH₂—NH—CH₂₁—CH₂—, —NH—CH₂CH₂CH₂— or —NH—;

Z is morpholin-4yl, dioxolan-2yl, tetrahydrofuranyl, pyridinyl,2-oxa-5-aza-bicyclo[2.2.1 ]hept-5yl, methoxyphenylpiperazinyl, hydroxy,methyl, N,N-dimethoxyethylamino, acetylamino, methylsulfonyl orcyanoethyl;

each R₁ is independently:

tert-butyl, sec-butyl, tert-amyl, phenyl,tetrahydropyran-2-yloxypropynyl, hydroxypropynyl, trihalomethyl,2,2-diethylpropionyl or cyclohexanyl;

R₂ is chloro, nitro, amino, nitrile, methylsulfonylamino, diacetylamino,phenylsulfonylamino, N,N-di(methylsulfonyl)amino, methylsulfonyl ortrihalomethylsulfonyl;

R₃ is independently:

methyl, C₁₋₃ alkoxy, methoxymethyl, hydroxypropyl, dimethylamino, Cl ₄alkylamino, NH₂C(O)methoxy, acetyl, pyrrolidinyl, imidazolyt, pyrazolyl,morpholino or morpholinocarbonyl.

In yet still even a further embodiment of the invention there isprovided compounds of the formula(III) as described immediately aboveand wherein:

X is pyridinyl.

In still even a further embodiment of the invention there is providedcompounds of the formula(III) as provided immediately above and wherein:

the pyridinyl is attached to Ar via the 3-pyridinyl position.

The following are representative compounds of the formula(Ill):

1-(4-tert-Butyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;

1-(5-tert-Butyl-2-methyl-phenyl)-3-[4-(4-morpholin-4-ylmethyl-piperidin-1-yl)-naphthalen-1-yl]-urea;

1-(6-Chloro-4-trifluoromethyl-pyridin-2-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;

1-(4-Difluoromethoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;

1-(3-Methyl-naphthalen-2-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;

1-[2-Methoxy-5-(1-methyl-1-phenyl-ethyl)-phenyl]-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;

(5-tert-Butyl-2-methyl-phenyl)-carbamic acid3-(5-{4-[3-(5-tert-butyl-2-methyl-phenyl)-ureido]-naphthalen-1-yl}-pyridin-2-ylamino)-propylester;

1-(6-tert-Butyl-benzo[1,3]dioxol-5-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;

N-(5-tert-Butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-ureido}-phenyl)-acetamide;

1,3-Bis-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;

1-[5-tert-Butyl-3-(2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-2-hydroxy-phenyl]-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;

1-[5-tert-Butyl-2-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;

1-[5-tert-Butyl-3-(2,3-dihydroxy-propyl)-2-hydroxy-phenyl]-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;

1-(2,3-Dimethyl-1H-indol-5-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;

1-[4-(6-Morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-3-(2-p-tolyloxy-5-trifluoromethyl-phenyl)-urea;

1-[2-(2-Methoxy-phenoxy)-5-trifluoromethyl-phenyl]-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;

1-[4-(6-Morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-3-naphthalen-1-yl-urea;

1-{5-tert-Butyl-2-methyl-3-[3-(tetrahydro-pyran-2-yloxy)-prop-1-ynyl]-phenyl}-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;

1-{5-tert-Butyl-2-[3-(tetrahydro-pyran-2-yloxy)-prop-1-ynyl]-phenyl}-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;

1-(5-Hydroxymethyl-2-methyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;

1-(2-Methoxy-dibenzofuran-3-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;

1-(2,5-Di-tert-butyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;

1-[3-(4-Bromo-1-methyl-1H-pyrazol-3-yl)-phenyl]-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;

1-(3-Hydroxy-5,6,7,8-tetrahydro-naphthalen-2-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;

1-(1-Acetyl-2,3-dihydro-1H-indol-5-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;

1-[4-(6-Morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-3-(3-oxazol-5-yl-phenyl)-urea;

1-[4-(6-Morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-3-(3-[1,3,4]oxadiazol-2-yl-phenyl)-urea;

1-(2-Methoxy-5-trifluoromethyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;

Furan-2-carboxylic acid(4-tert-butyl-2-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-ureido}-phenyl)-amide;

1-(2-Methoxy-4-phenylamino-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;

1-(5-Methoxy-2-methyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;

1-(3-Hydroxy-naphthalen-2-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;

N,N-Diethyl-4-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-ureido}-benzenesulfonamide;

1-(2,2-Difluoro-benzo[1,3]dioxol-5-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;

1-[5-(1,1-Dimethyl-propyl)-2-phenoxy-phenyl]-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;

1-[5-(2,2-Dimethyl-propionyl)-2-methyl-phenyl]-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;

2-Chloro-5-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-ureido}-benzoicacid isopropyl ester;

1-(4-Amino-3,5-dibromo-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;

1-[5-tert-Butyl-3-(3-hydroxy-prop-1-ynyl)-2-methyl-phenyl]-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;

1-[5-tert-Butyl-2-(3-hydroxy-prop-1-ynyl)-phenyl]-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;

1-[5-tert-Butyl-3-(2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-2-methoxy-phenyl]-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;

1-[5-tert-Butyl-3-(2,3-dihydroxy-propyl)-2-methoxy-phenyl]-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;

1-(5-tert-Butoxy-2-methoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;

1-[5-(1-Cyano-cyclopropyl)-2-methoxy-phenyl]-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;

1-[5-tert-Butyl-3-(2-diethylamino-ethyl)-2-methoxy-phenyl]-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;

1-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(6-[1,3]dioxolan-2-yl-pyridin-3-yl)-naphthalen-1-yl]-urea;

1-(5-tert-Butyl-2-pyrrolidin-1-yl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;

1-(5-tert-Butyl-2-dimethylamino-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;

1-(5-tert-Butyl-2-propoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;

1-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(6-hydroxymethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;

1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(2,6-dimethyl-morpholin-4-ylmethyl)-pyridin-3-yl]-naphthalen-1-yl}-urea;

2-(5-tert-Butyl-2-methoxy-phenyl)-N-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-acetamide;

1-(2-Methoxy-5-phenoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;

1-(3,3-Dimethyl-2-oxo-2,3-dihydro-1H-indol-7-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;

1-(5-tert-Butyl-2-cyclopentyloxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;

1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(3-pyridin-3-yl-pyrrolidin-1-ylmethyl)-pyridin-3-yl]-naphthalen-1-yl}-urea;

1-(5-Cyclohexyl-2-methoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;

1-(2,4-Dimethoxy-5-trifluoromethyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;

1-(6-tert-Butyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-7-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;

1-(5-tert-Butyl-2-methoxy-3-nitro-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;

1-(3-Amino-5-tert-butyl-2-methoxy-phenyl)-3-[4-(6-methyl-pyridin-3-yl)-naphthalen-1-yl]-urea;

N-Acetyl-N-(5-tert-butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-ureido}-phenyl)-acetamide;

1-(6-tert-Butyl-4-methyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;

1-[6-tert-Butyl-4-(2-morpholin-4-yl-ethyl)-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl]-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;

1-(5-tert-Butyl-2-ethoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;

1-(5-tert-Butyl-2-isopropoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;

1-(5-tert-Butyl-2-imidazol-1-yl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;

N-(5-tert-Butyl-2-methoxy-4-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-ureido}-phenyl)-methanesulfonamide;

1-(5-tert-Butyl-3-ethylamino-2-methoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;

N-(5-tert-Butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-ureido}-phenyl)-bis(methanesulfon)amide;

1-[5-tert-Butyl-2-(1-methyl-1H-pyrazol-4-yl)-phenyl]-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;

1-(2-Methanesulfinyl-5-trifluoromethyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;

1-(2-Ethanesulfonyl-5-trifluoromethyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;

1-[4-(6-{ [Bis-(2-methoxy-ethyl)-amino]-methyl}-pyridin-3-yl)-naphthalen-1-yl]-3-(5-tert-butyl-2-methoxy-phenyl)-urea;

1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(3-dimethylamino-pyrrolidin-1-ylmethyl)-pyridin-3-yl]-naphthalen-1-yl}-urea;

N-[1-(5-{4-[3-(5-tert-Butyl-2-methoxy-phenyl)-ureido]-naphthalen-1-yl}-pyridin-2-ylmethyl)-pyrrolidin-3-yl]-acetamide;

1-(1-Acetyl-3,3-dimethyl-2,3-dihydro-1H-indol-5-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;

N-(5-tert-Butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-ureido}-phenyl)-propionamide;

1-(5-tert-Butyl-2-methyl-benzooxazol-7-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;

1-[4-(6-Morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-3-(3-trifluoromethanesulfonyl-phenyl)-urea;

N-(5-tert-Butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-ureido}-phenyl)-isobutyramide;

2-(4-tert-Butyl-2-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-ureido}-phenoxy)-acetamide;

1-(5-tert-Butyl-2-oxo-2,3-dihydro-benzooxazol-7-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;

1-(6-tert-Butyl-3-cyano-2-methoxymethoxy-pyridin-4-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;

1-(6-tert-Butyl-3-cyano-2-hydroxy-pyridin-4-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;

1-(5-tert-Butyl-3-cyano-2-methoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;

1-[4-(6-Morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-3-(1,3,3-trimethyl-2,3-dihydro-1H-indol-5-yl)-urea;

1-(5-tert-Butyl-benzooxazol-7-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;

N-(5-tert-Butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-ureido}-phenyl)-benzenesulfonamide;

Ethanesulfonic acid(5-tert-butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-ureido}-phenyl)-amide;

1-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(4-morpholin-4-ylmethyl-piperidin-1-yl)-naphthalen-1-yl]-urea;

1-[5-tert-Butyl-2-(1-methyl-1H-pyrazol-4-yl)-phenyl]-3-[4-(4-morpholin-4-piperidin-1-yl)-naphthalen-1-yl]-urea;

1-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(2-morpholin-4-ylmethyl-pyrimidin-5-yl)-naphthalen-1-yl]-urea;

1-(5-tert-Butyl-2-methylsulfanyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;

1-(5-tert-Butyl-2-methoxy-pyridin-3-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;

2,2,2-Trifluoro-ethanesulfonic acid(5-tert-butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-ureido}-phenyl)-amide;

N-(5-{4-[3-(5-tert-Butyl-2-methyl-phenyl)-ureido]-naphthalen-1-yl}-pyrazin-2-yl)-methanesulfonamide;

1-[4-(6-{[Bis-(2-cyano-ethyl)-amino]-methyl}-pyridin-3-yl)-naphthalen-1-yl]-3-(5-tert-butyl-2-methoxy-phenyl)-urea;

1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(4-methyl-piperazin-1-ylmethyl)-pyridin-3-yl]-naphthalen-1-yl}-urea;

1-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(6-thiomorpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;

1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(2,6-dimethyl-piperidin-1-ylmethyl)-pyridin-3-yl]-naphthalen-1-yl}-urea;

1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(1-oxo-tetrahydro-thiopyran-4-ylamino)-pyridin-3-yl]-naphthalen-1-yl}-urea;

1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(tetrahydro-pyran-4-ylamino)-pyridin-3-yl]-naphthalen-1-yl}-urea;

1-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(6-{[(2-cyano-ethyl)-(tetrahydro-furan-2-ylmethyl)-amino]-methyl}-pyridin-3-yl)-naphthalen-1-yl]-urea;

1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(2-methoxymethyl-morpholin-4-ylmethyl)-pyridin-3-yl]-naphthalen-1-yl}-urea;

1-(5-tert-Butyl-2-methoxy-phenyl)-3-(4-{6-[(2-morpholin-4-yl-ethylamino)-methyl]-pyridin-3-yl}-naphthalen-1-yl)-urea;

1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(2-methyl-3-oxo-piperazin-1-ylmethyl)-pyridin-3-yl]-naphthalen-1-yl}-urea;

1-(5-{4-[3-(5-tert-Butyl-2-methoxy-phenyl)-ureido]-naphthalen-1-yl}-pyridin-2-ylmethyl)-piperidine-3-carboxylic acid amide;

1-(5-{4-[3-(5-tert-Butyl-2-methoxy-phenyl)-ureido]-naphthalen-1-yl}-pyridin-2-ylmethyl)-piperidine-4-carboxylicacid amide;

1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(1-oxo-114-thiomorpholin-4-ylmethyl)-pyridin-3-yl]-naphthalen-1-yl}-urea;

1-(3,3-Dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;

1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(3-oxo-piperazin-1-ylmethyl)-pyridin-3-yl]-naphthalen-1-yl}-urea;

1-{4-[6-(4-Acetyl-piperazin-1-ylmethyl)-pyridin-3-yl]-naphthalen-1-yl}-3-(5-tert-butyl-2-methoxy-phenyl)-urea;

4-(5-{4-[3-(5-tert-Butyl-2-methoxy-phenyl)-ureido]-naphthalen-1-yl}-pyridin-2-ylmethyl)-piperazine-1-carboxylicacid ethyl ester;

1-(5-tert-Butyl-2-methoxy-phenyl)-3-(4-{6-[(2-pyridin-3-yl-ethylamino)-methyl]-pyridin-3-yl}-naphthalen-1-yl)-urea;

1-(5-tert-Butyl-2-methoxy-phenyl)-3-(4-{6-[(tetrahydro-furan-3-ylamino)-methyl]-pyridin-3-yl}-naphthalen-1-yl)-urea;

1-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(6-{[(2-cyano-ethyl)-pyridin-3-ylmethyl-amino]-methyl}-pyridin-3-yl)-naphthalen-1-yl]-urea;

1-(5-tert-Butyl-2-methoxy-phenyl)-3-(4-{6-[(2-methylsulfanyl-ethylamino)-methyl]-pyridin-3-yl}-naphthalen-1-yl)-urea;

1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(2-oxa-5-aza-bicyclo[2.2.1]hept-5-ylmethyl)-pyridin-3-yl]-naphthalen-1-yl}-urea;

1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(2,6-dimethyl-morpholin-4-ylmethyl)-pyridin-3-yl]-naphthalen-1-yl}-urea;

1-(5-tert-Butyl-2-methoxy-phenyl)-3-(4-{6-[(2-piperazin-1-yl-ethylamino)-methyl]-pyridin-3-yl}-naphthalen-1-yl)-urea;

1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(4-pyrimidin-2-yl-piperazin-1-ylmethyl)-pyridin-3-yl]-naphthalen-1-yl}-urea;

1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(4-pyridin-2-yl-piperazin-1-ylmethyl)-pyridin-3-yl]-naphthalen-1-yl}-urea;

1-(5-tert-Butyl-2-methoxy-phenyl)-3-(4-{6-[4-(3-methoxy-phenyl)-piperazin-1-ylmethyl]-pyridin-3-yl}-naphthalen-1-yl)-urea;

1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(morpholine-4-carbonyl)-pyridin-3-yl]-naphthalen-1-yl}-urea;

1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(2-thia-5-aza-bicyclo[2.2.1]hept-5-ylmethyl)-pyridin-3-yl]-naphthalen-1-yl}-urea;

1-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(5-morpholin-4-ylmethyl-pyrazin-2-yl)-naphthalen-1-yl]-urea;

1-(6-tert-Butyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;

1-(3-Amino-5-tert-butyl-2-methoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;

N-(5-{4-[3-(5-tert-Butyl-2-methoxy-phenyl)-ureido]-naphthalen-1-yl}-pyridin-2-yl)-acetamide;

N-(5-tert-Butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-ureido}-phenyl)-N-methyl-acetamide;

N-(5-tert-Butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-ureido}-phenyl)-2,2,2-trifluoro-acetamide;

1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(pyridin-3-yloxy)-pyridin-3-yl]-naphthalen-1-yl}-urea;

1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(pyridin-3-ylamino)-pyridin-3-yl]-naphthalen-1-yl}-urea;

[4-(6-Morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-carbamic acid3-tert-butyl-phenyl ester;

N-(5-tert-Butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-ureido}-phenyl)-methanesulfonamideand

and the pharmaceutically acceptable derivatives thereof.

In yet another embodiment of the invention there is provided thefollowing compounds of the formula(III):

1-(3-Methyl-naphthalen-2-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;

N-(5-tert-Butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-ureido}-phenyl)-acetamide;

1-[5-tert-Butyl-3-(2,3-dihydroxy-propyl)-2-hydroxy-phenyl]-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;

1-(2,3-Dimethyl-1H-indol-5-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;

1-{5-tert-Butyl-2-methyl-3-[3-(tetrahydro-pyran-2-yloxy)-prop-1-ynyl]-phenyl}-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;

1-(2-Methoxy-5-trifluoromethyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;

1-[5-(2,2-Dimethyl-propionyl)-2-methyl-phenyl]-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;

1-[5-tert-Butyl-3-(3-hydroxy-prop-1-ynyt)-2-methyl-phenyl]-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;

1-[5-tert-Butyl-2-(3-hydroxy-prop-1-ynyl)-phenyl]-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;

1-[5-tert-Butyl-3-(2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-2-methoxy-phenyl]-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;

1-[5-tert-Butyl-3-(2,3-dihydroxy-propyl)-2-methoxy-phenyl]-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;

1-(5-tert-Butoxy-2-methoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;

1-[5-(1-Cyano-cyclopropyl)-2-methoxy-phenyl]-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;

1-[5-tert-Butyl-3-(2-diethylamino-ethyl)-2-methoxy-phenyl]-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;

1-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(6-[1,3]dioxolan-2-yl-pyridin-3-yl)-naphthalen-1-yl]-urea;

1-(5-tert-Butyl-2-pyrrolidin-1-yl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;

1-(5-tert-Butyl-2-dimethylamino-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;

1-(5-tert-Butyl-2-propoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;

1-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(6-hydroxymethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;

1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(2,6-dimethyl-morpholin-4-ylmethyl)-pyridin-3-yl]-naphthalen-1-yl}-urea;

1-(5-Cyclohexyl-2-methoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;

1-(2,4-Dimethoxy-5-trifluoromethyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;

1-(5-tert-Butyl-2-methoxy-3-nitro-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;

1-(3-Amino-5-tert-butyl-2-methoxy-phenyl)-3-[4-(6-methyl-pyridin-3-yl)-naphthalen-1-yl]-urea;

N-Acetyl-N-(5-tert-butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-ureido}-phenyl)-acetamide;

1-(6-tert-Butyl-4-methyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;

1-(5-tert-Butyl-2-ethoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;

1-(5-tert-Butyl-2-isopropoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;

1-(5-tert-Butyl-2-imidazol-1-yl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;

1-(5-tert-Butyl-3-ethylamino-2-methoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;

N-(5-tert-Butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-ureido}-phenyl)-bis(methanesulfon)amide;

1-[5-tert-Butyl-2-(1-methyl-1H-pyrazol-4-yl)-phenyl]-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;

1-(2-Methanesulfinyl-5-trifluoromethyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;

1-[4-(6-{[Bis-(2-methoxy-ethyl)-amino]-methyl}-pyridin-3-yl)-naphthalen-1-yl]-3-(5-tert-butyl-2-methoxy-phenyl)-urea;

N-[1-(5-{4-[3-(5-tert-Butyl-2-methoxy-phenyl)-ureido]-naphthalen-1-yl}-pyridin-2-ylmethyl)-pyrrolidin-3-yl]-acetamide;

1-(1-Acetyl-3,3-dimethyl-2,3-dihydro-1H-indol-5-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;

N-(5-tert-Butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-ureido}-phenyl)-propionamide;

1-(5-tert-Butyl-2-methyl-benzooxazol-7-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;

1-[4-(6-Morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-3-(3-trifluoromethanesulfonyl-phenyl)-urea;

N-(5-tert-Butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-ureido}-phenyl)-isobutyramide;

2-(4-tert-Butyl-2-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-ureido}-phenoxy)-acetamide;

1-(5-tert-Butyl-2-oxo-2,3-dihydro-benzooxazol-7-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;

1-(5-tert-Butyl-3-cyano-2-methoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;

1-(5-tert-Butyl-benzooxazol-7-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;

N-(5-tert-Butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-ureido}-phenyl)-benzenesulfonamide;

Ethanesulfonic acid(5-tert-butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-ureido}-phenyl)-amide;

1-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(2-morpholin-4-ylmethyl-pyrimidin-5-yl)-naphthalen-1-yl]-urea;

1-(5-tert-Butyl-2-methylsulfanyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;

1-(5-tert-Butyl-2-methoxy-pyridin-3-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;

2,2,2-Trifluoro-ethanesulfonic acid(5-tert-butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-ureido}-phenyl)-amide;

N-(5-{4-[3-(5-tert-Butyl-2-methyl-phenyl)-ureido]-naphthalen-1-yl}-pyrazin-2-yl)-methanesulfonamide;

1-[4-(6-{[Bis-(2-cyano-ethyl)-amino]-methyl}-pyridin-3-yl)-naphthalen-1-yl]-3-(5-tert-butyl-2-methoxy-phenyl)-urea;

1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(4-methyl-piperazin-1-ylmethyl)-pyridin-3-yl]-naphthalen-1-yl}-urea;

1-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(6-thiomorpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;

1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(2,6-dimethyl-piperidin-1-ylmethyl)-pyridin-3-yl]-naphthalen-1-yl}-urea;

1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(1-oxo-tetrahydro-thiopyran-4-ylamino)-pyridin-3-yl]-naphthalen-1-yl}-urea;

1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(tetrahydro-pyran-4-ylamino)-pyridin-3-yl]-naphthalen-1-yl}-urea;

1-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(6-{[(2-cyano-ethyl)-(tetrahydro-furan-2-ylmethyl)-amino]-methyl}-pyridin-3-yl)-naphthalen-1-yl]-urea;

1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(2-methoxymethyl-morpholin-4-ylmethyl)-pyridin-3-yl]-naphthalen-1-yl}-urea;

1(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(2-methyl-3-oxo-piperazin-1-ylmethyl)-pyridin-3-yl]-naphthalen-1-yl}-urea;

1-(5-{4-[3-(5-tert-Butyl-2-methoxy-phenyl)-ureido]-naphthalen-1-yl}-pyridin-2-ylmethyl)-piperidine-3-carboxylicacid amide;

1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(1-oxo-114-thiomorpholin-4-ylmethyl)-pyridin-3-yl]-naphthalen-1-yl}-urea;

1-(3,3-Dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-3-[4-(6-morpholin-4-ylmethyl)-pyridin-3-yl)-naphthalen-1-yl]-urea;

1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(3-oxo-piperazin-1-ylmethyl)-pyridin-3-yl]-naphthalen-1-yl}-urea;

1-(5-tert-Butyl-2-methoxy-phenyl)-3-(4-{6-[(tetrahydro-furan-3-ylamino)-methyl]-pyridin-3-yl}-naphthalen-1-yl)-urea;

1-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(6-{[(2-cyano-ethyl)-pyridin-3-ylmethyl-amino]-methyl}-pyridin-3-yl)-naphthalen-1-yl]-urea;

1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(2-oxa-5-aza-bicyclo[2.2.1]hept-5-ylmethyl)-pyridin-3-yl]-naphthalen-1-yl}-urea;

1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(2,6-dimethyl-morpholin-4-ylmethyl)-pyridin-3-yl]-naphthalen-1-yl}-urea;

1-(5-tert-Butyl-2-methoxy-phenyl)-3-(4-{6-[4-(3-methoxy-phenyl)-piperazin-1-ylmethyl]-pyridin-3-yl}-naphthalen-1-yl)-urea;

1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(morpholine-4-carbonyl)-pyridin-3-yl]-naphthalen-1-yl}-urea;

1-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(5-morpholin-4-ylmethyl-pyrazin-2-yl)-naphthalen-1-yl]-urea;

1-(6-tert-Butyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;

1-(3-Amino-5-tert-butyl-2-methoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;

N-(5-{4-[3-(5-tert-Butyl-2-methoxy-phenyl)-ureido]-naphthalen-1-yl}-pyridin-2-yl)-acetamide;

N-(5-tert-Butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-ureido}-phenyl)-N-methyl-acetamide;

N-(5-tert-Butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-ureido}-phenyl)-2,2,2-trifluoro-acetamide;

1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(pyridin-3-yloxy)-pyridin-3-yl]-naphthalen-1-yl}-urea;

[4-(6-Morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-carbamic acid3-tert-butyl-phenyl ester;

N-(5-tert-Butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-ureido}-phenyl)-methanesulfonamideand

and the pharmaceutically acceptable derivatives thereof.

In addtion to the abovementioned compounds the following propheticcompounds of the formula(III) may be made by the general methodsdescribed hereinbelow:

1-(5-tert-Butyl-2-methylsulfanyl-pyridin-3-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;

1-(5-tert-Butyl-2-chloro-pyridin-3-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;

1-(5-tert-Butyl-2-methylamino-pyridin-3-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;

N-(5-tert-Butyl-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-ureido}-2-oxo-2H-pyridin-1-yl)-methanesulfonamide;

5-tert-Butyl-7-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-ureido}-benzooxazole-2-carboxylicacid amide;

2-(5-tert-Butyl-7-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-ureido}-benzooxazol-2-yl)-acetamide;

5-tert-Butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-ureido}-benzamideand

and the pharmaceutically acceptable derivatives thereof.

Any compounds of this invention containing one or more asymmetric carbonatoms may occur as racemates and racemic mixtures, single enantiomers,diastereomeric mixtures and individual diastereomers. All such isomericforms of these compounds are expressly included in the presentinvention. Each stereogenic carbon may be in the R or S configuration,or a combination of configurations.

Some of the compounds of formulas (I), (Ia), (II) and (III) can exist inmore than one tautomeric form. The invention includes all suchtautomers.

All terms as used herein in this specification, unless otherwise stated,shall be understood in their ordinary meaning as known in the art. Forexample, “C₁₋₄alkoxy” is a C₁₋₄ alkyl with a terminal oxygen, such asmethoxy, ethoxy, propoxy, pentoxy and hexoxy. All alkyl, alkenyl andalkynyl groups shall be understood as being branched or unbranched wherestructurally possible and unless otherwise specified. Other morespecific definitions are as follows:

The term “aroyl” as used in the present specification shall beunderstood to mean “benzoyl” or “naphthoyl”.

The term “carbocycle” shall be understood to mean an aliphatichydrocarbon radical containing from three to twelve carbon atoms.Carbocycles include hydrocarbon rings containing from three to tencarbon atoms. These carbocycles may be either aromatic and non-aromaticring systems. The non-aromatic ring systems may be mono- orpolyunsaturated. Preferred carbocycles include but are not limited tocyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl,cyclohexenyl, cycloheptanyl, cycloheptenyl, phenyl, indanyl, indenyl,benzocyclobutanyl, dihydronaphthyl, tetrahydronaphthyl, naphthyl,decahydronaphthyl, benzocycloheptanyl and benzocycloheptenyl. Certainterms for cycloalkyl such as cyclobutanyl and cyclobutyl shall be usedinerchangeably.

The term “heterocycle” refers to a stable nonaromatic 4-8 membered (butpreferably, 5 or 6 membered) monocyclic or nonaromatic 8-11 memberedbicyclic heterocycle radical which may be either saturated orunsaturated. Each heterocycle consists of carbon atoms and one or more,preferably from 1 to 4 heteroatoms selected from nitrogen, oxygen andsulfur. The heterocycle may be attached by any atom of the cycle, whichresults in the creation of a stable structure. Unless otherwise stated,heterocycles include but are not limited to, for example oxetanyl,pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl,piperazinyl, morpholinyl, tetrahydropyranyl, dioxanyl, tetramethylenesulfonyl, tetramethylene sulfoxidyl, oxazolinyl, thiazolinyl,imidazolinyl, tertrahydropyridinyl, homopiperidinyl, pyrrolinyl,tetrahydropyrimidinyl, decahydroquinolinyl, decahydroisoquinolinyl,thiomorpholinyl, thiazolidinyl, dihydrooxazinyl, dihydropyranyl,oxocanyl, heptacanyl, thioxanyl, dithianyl or 2-oxa- or2-thia-5-aza-bicyclo[2.2.1]heptanyl.

The term “heteroaryl” shall be understood to mean an aromatic 5-8membered monocyclic or 8-11 membered bicyclic ring containing 1-4heteroatoms such as N, O and S. Unless otherwise stated, suchheteroaryls include: pyridinyl, pyridonyl, quinolinyl,dihydroquinolinyl, tetrahydroquinoyl, isoquinolinyl,tetrahydroisoquinoyl, pyridazinyl, pyrimidinyl, pyrazinyl,benzimidazolyl, benzthiazolyl, benzoxazolyl, benzofuranyl,benzothiophenyl, benzpyrazolyl, dihydrobenzofuranyl,dihydrobenzothiophenyl, benzooxazolonyl, benzo[1,4]oxazin-3-onyl,benzodioxolyl, benzo[1,3]dioxol-2-onyl, tetrahydrobenzopyranyl, indolyl,indolinyl, indolonyl, indolinonyl, phthalimidyl.

The term “heteroatom” as used herein shall be understood to mean atomsother than carbon such as O, N, S and P.

The term “aryl” as used herein shall be understood to mean aromaticcarbocycle or heteroaryl as defined herein.

Terms which are analogs of the above cyclic moieties such as aryloxy orheteroaryl amine shall be understood to mean an aryl, heteroaryl,heterocycle as defined above attached to it's respective group.

As used herein, “nitrogen” and “sulfur” include any oxidized form ofnitrogen and sulfur and the quaternized form of any basic nitrogen.

The term “halogen” as used in the present specification shall beunderstood to mean bromine, chlorine, fluorine or iodine.

The compounds of the invention are only those which are contemplated tobe ‘chemically stable’ as will be appreciated by those skilled in theart. For example, a compound which would have a ‘dangling valency’, or a‘carbanion’ are not compounds contemplated by the invention.

The invention includes pharmaceutically acceptable derivatives ofcompounds of formula (I), (Ia), (II) and (III). A “pharmaceuticallyacceptable derivative” refers to any pharmaceutically acceptable salt orester of a compound of this invention, or any other compound which, uponadministration to a patient, is capable of providing (directly orindirectly) a compound of this invention, a pharmacologically activemetabolite or pharmacologically active residue thereof. Apharmacologically active metabolite shall be understood to mean anycompound of the invention capable of being metabolized enzymatically orchemically. This includes, for example, hydroxylated or oxidizedderivative compounds of the formulas(I), (Ia), (II) or (III).

Pharmaceutically acceptable salts of the compounds of this inventioninclude those derived from pharmaceutically acceptable inorganic andorganic acids and bases. Examples of suitable acids includehydrochloric, hydrobromic, sulfuric, nitric, perchloric, fumaric,maleic, phosphoric, glycolic, lactic, salicylic, succinic,toluene-p-sulfuric, tartaric, acetic, citric, methanesulfonic, formic,benzoic, malonic, naphthalene-2-sulfuric and benzenesulfonic acids.Other acids, such as oxalic acid, while not themselves pharmaceuticallyacceptable, may be employed in the preparation of salts useful asintermediates in obtaining the compounds of this invention and theirpharmaceutically acceptable acid addition salts. Salts derived fromappropriate bases include alkali metal (e.g., sodium), alkaline earthmetal (e.g., magnesium), ammonium and N—(C₁-C₄ alkyl)₄ ⁺ salts.

In addition, the compounds of this invention include prodrugs ofcompounds of the formula (I), (Ia), (II) and (III). Prodrugs includethose compounds that, upon simple chemical transformation, are modifiedto produce compounds of the invention. Simple chemical transformationsinclude hydrolysis, oxidation and reduction. Specifically, when aprodrug of this invention is administered to a patient, the prodrug maybe transformed into a compound of the invention, thereby imparting thedesired pharmacological effect.

METHODS OF USE

In accordance with the invention, there are provided methods of usingthe compounds of the formulas (I), (Ia), (II) and (III). The compoundsof the invention effectively block inflammatory cytokine production fromcells. The inhibition of cytokine production is an attractive means forpreventing and treating a variety of disorders associated with excesscytokine production, e.g., diseases and pathological conditionsinvolving inflammation. Thus, the compounds of the invention are usefulfor the treatment of such conditions. These encompass chronicinflammatory diseases including, but not limited to, osteoarthritis,multiple sclerosis, Guillain-Barre syndrome, Crohn's disease, ulcerativecolitis, psoriasis, graft versus host disease, systemic lupuserythematosus and insulin-dependent diabetes mellitus. The compounds ofthe invention can also be used to treat other disorders associated withthe activity of elevated levels of proinflammatory cytokines such asresponses to various infectious agents and a number of diseases ofautoimmunity such as rheumatoid arthritis, toxic shock syndrome,diabetes and inflammatory bowel diseases unrelated to those listed aboveare discussed in the Background of the Invention.

In addition, the compounds of the invention being inhibitors of cytokineproduction are expected to block inducible cyclooxygenase (COX-2)expression. COX-2 expression has been shown to be increased by cytokinesand it is believed to be the isoform of cyclooxygenase responsible forinflammation (M. K. O'Banion et al., Proc. Natl. Acad. Sci. U.S.A, 1992,89, 4888.) Accordingly, the present novel compounds would be expected toexhibit efficacy against those disorders currently treated with COXinhibitors such as the familiar NSAIDs. These disorders include acuteand chronic pain as well as symptoms of inflammation and cardiovasculardisease.

As discussed in the Background of the Invention, IL-8 plays a role inthe influx of neutrophils into sites of inflammation or injury.Therefore, in a yet further aspect of the invention, the compounds ofthe invention may be useful in the treatment of diseases mediatedpredominantly by neutrophils such as stroke and myocardial infarction,alone or following thrombolytic therapy, thermal injury, adultrespiratory distress syndrome (ARDS), multiple organ injury secondary totrauma, acute glomerulonephritis, dermatoses with acute inflammatorycomponents, acute purulent meningitis or other central nervous systemdisorders, hemodialysis, leukopherisis, granulocyte transfusionassociated syndromes, and necrotizing entrerocolitis.

For therapeutic use, the compounds of the invention may be administeredin any conventional dosage form in any conventional manner. Routes ofadministration include, but are not limited to, intravenously,intramuscularly, subcutaneously, intrasynovially, by infusion,sublingually, transdermally, orally, topically or by inhalation. Thepreferred modes of administration are oral and intravenous.

The compounds of this invention may be administered alone or incombination with adjuvants that enhance stability of the inhibitors,facilitate administration of pharmaceutic compositions containing themin certain embodiments, provide increased dissolution or dispersion,increase inhibitory activity, provide adjunct therapy, and the like,including other active ingredients. Advantageously, such combinationtherapies utilize lower dosages of the conventional therapeutics, thusavoiding possible toxicity and adverse side effects incurred when thoseagents are used as monotherapies. Compounds of the invention may bephysically combined with the conventional therapeutics or otheradjuvants into a single pharmaceutical composition. Advantageously, thecompounds may then be administered together in a single dosage form. Insome embodiments, the pharmaceutical compositions comprising suchcombinations of compounds contain at least about 5%, but more preferablyat least about 20%, of a compound of formulas (I), (Ia), (II) or (III)(w/w) or a combination thereof. The optimum percentage (w/w) of acompound of the invention may vary and is within the purview of thoseskilled in the art. Alternatively, the compounds may be administeredseparately (either serially or in parallel). Separate dosing allows forgreater flexibility in the dosing regime.

As mentioned above, dosage forms of the compounds of this inventioninclude pharmaceutically acceptable carriers and adjuvants known tothose of ordinary skill in the art. These carriers and adjuvantsinclude, for example, ion exchangers, alumina, aluminum stearate,lecithin, serum proteins, buffer substances, water, salts orelectrolytes and cellulose-based substances. Preferred dosage formsinclude, tablet, capsule, caplet, liquid, solution, suspension,emulsion, lozenges, syrup, reconstitutable powder, granule, suppositoryand transdermal patch. Methods for preparing such dosage forms are known(see, for example, H. C. Ansel and N. G. Popovish, Pharmaceutical DosageForms and Drug Delivery Systems, 5th ed., Lea and Febiger (1990)).Dosage levels and requirements are well-recognized in the art and may beselected by those of ordinary skill in the art from available methodsand techniques suitable for a particular patient. In some embodiments,dosage levels range from about 1-1000 mg/dose for a 70 kg patient.Although one dose per day may be sufficient, up to 5 doses per day maybe given. For oral doses, up to 2000 mg/day may be required. As theskilled artisan will appreciate, lower or higher doses may be requireddepending on particular factors. For instance, specific dosage andtreatment regimens will depend on factors such as the patient's generalhealth profile, the severity and course of the patient's disorder ordisposition thereto, and the judgment of the treating physician.

In order that this invention be more fully understood, the followingexamples are set forth. These examples are for the purpose ofillustrating preferred embodiments of this invention, and are not to beconstrued as limiting the scope of the invention in any way.

The examples which follow are illustrative and, as recognized by oneskilled in the art, particular reagents or conditions could be modifiedas needed for individual compounds. Starting materials used in thescheme below are either commercially available or easily prepared fromcommercially available materials by those skilled in the art.

GENERAL SYNTHETIC METHODS

The compounds of the invention may be prepared by Method A, B, or C asillustrated in Scheme I, preferably method C. Further reference in thisregard may be made to PCT application number PCT/US99/29165, U.S.Provisional application Nos. 60/124,148 and 60/165,867, and attorneydocket numbers 9/183 for Kapadia et al and 9/184 for Kapadia et al. Eachof the aforementioned incorporated herein by reference in theirentirety.

In Method A, a mixture of an amine of formula IV and an isocyanate offormula V is dissolved in a non-protic, anhydrous solvent such as THF,ether, toluene, dioxane or ethyl acetate. The preferred solvent is THF.The mixture is stirred at between 0-45° C., preferably at 25° C., for2-24 hr, and the volatiles are removed. Purification of the residue byrecrystallization from an appropriate solvent such as ethylacetate/hexanes, ethyl acetate/methanol, THF/petroleum ether,ethanol/water or by silica gel chromatography, using for example,hexanes and ethyl acetate as eluents, provides the product of formula I,Ia, II or III (E═NH).

In Method B, an amine of formula IV is dissolved in a halogenatedsolvent, such as methylene chloride, chloroform or dichloroethane. Thepreferred solvent is methylene chloride. The mixture is diluted withaqueous alkali, such as sodium bicarbonate or potassium carbonate,cooled in an ice bath and phosgene is added. The mixture is vigorouslystirred for 5-30 min, with 10 min being preferable. The organic layer isdried, with agents such as MgSO₄ or Na₂SO₄, and the volatiles removed toprovide the corresponding isocyanate, D-N═C═O. The isocyanate and amineVI are mixed in a non-protic, anhydrous solvent such as THF, ether,toluene, dioxane, methylene chloride or ethyl acetate. The preferredsolvent is THF. The mixture is stirred at between 0-45° C., preferablyat 25° C., for 2-24 hr, and the volatiles are removed. Purification ofthe residue by recrystallization or by silica gel chromatography, asabove, provides the product of formula I, Ia, II or III (E═NH).

The required isocyanate may also be prepared from the carboxylic acidD-CO₂H by reaction with a chloroformate, such as ethyl chloroformate, inthe presence of a suitable base, such as triethylamine, in a suitablesolvent, such as THF at about 0° C. The resulting mixed anhydride istreated with an aqueous solution of sodium azide. Heating a solution ofthe resulting acyl azide in a suitable solvent, such as toluene, atabout reflux, results in a Curtius rearrangement, providing theisocyanate D-N═C═O in situ.

In Method C, an amine of formula IV is dissolved in a suitable solventsuch as a halogenated solvent such as methylene chloride, chloroform ordichloroethane. The preferred solvent is methylene chloride. A suitablebase such as triethylamine may be added, followed by phenylchloroformate. The mixture is stirred at between 0-85° C., preferably atreflux temperature, for 2-24 hr, and the volatiles are removed providingcarbamate VII. The carbamate and amine VI are mixed in a non-protic,anhydrous solvent such as THF, ether, toluene, dioxane, methylenechloride or ethyl acetate. The preferred solvent is THF. The mixture isstirred at between 0-110° C., preferably at reflux temperature, for 2-24hr, and the volatiles are removed. Purification of the residue as aboveprovides the product of formula I, Ia, II or III (E=NH). This Method mayalso be employed in the reverse sense, that is one may form thecarbamate from D′NH₂ and react this carbamate with amine D-NH₂. Example37 illustrates the synthesis of a compound of formula III in which E is—O—, and Example 38 illustrates the synthesis of a compound of formulaIII in which E is —CH₂—.

The method used to produce amines of formula IV will depend on thenature of the desired group D. In general, intermediates of formula IVcan be made by methods known to those skilled in the art. Some generalmethods are illustrated in the schemes below. Compounds D′-NCO or D′-NH₂in Scheme I may be commercially available, or may be prepared by methodsknown to those skilled in the art. If D′ is a precursor of Ar₂—X—Y—Z orAr—X—Y—Z, the desired final product of formula I, Ia, II or III may beconstructed by methods known to those skilled in the art. Illustrativeexamples are contained in the Synthetic Examples section below.

Desired aminopyrazoles of formula XV, for use in preparation ofcompounds of formula I or Ia, can be prepared as described in Scheme II.A hydrazine of formula X, bearing substituent R₃, may be prepared byMethod D or E. In Method D, an aryl bromide of formula VIII is dissolvedin a non-protic, inert solvent, such as THF, 1,4-dioxane or diethylether, and cooled to low temperature under an inert atmosphere. Thepreferred temperature for the solution is −77° C. A strong basedissolved in a non-protic, inert solvent, such as hexanes, THF or ether,is added dropwise while maintaing a reaction temperature below 0° C. andpreferrably below −60° C. The preferred bases are alkyl lithium reagentsand the most preferred is sec-butyl lithium. After the addition of thebase, the reaction mixture is stirred for a period of time betweenthirty and ninety min or until all the starting aryl bromide has beenconsumed. An excess of dialkyl azodicarboxylate is added whilemaintaining a reaction temperature below 0° C. and preferrably below−60° C. The preferred dialkyl azodicarboxylate is di-tert-butylazodicarboxylate. The reaction is stirred at cold temperatures andwarmed to room temperature after 0.5 h to 2 hr. The reaction is quenchedwith the addition of water and the product extracted into a non-proticsolvent, such as ethyl acetate, diethyl ether or chloroform. The organiclayers are dried with agents such as MgSO₄ or Na₂SO₄ and the volatilesremoved. The residue is dissolved in protic solvents, such as methanolor iso-propanol, cooled, preferably to 0-5° C. and treated with acid.Preferred acids are hydrochloric, hydrobromic, sulfuric andtrifluoroacetic. The most preferred is hydrochloric acid in gaseousform. After the addition of excess acid the mixture is heated at thereflux temperature of the solvent until all starting material has beenconsumed. After cooling the product aryl-hydrazine salt of formula X isfiltered and dried.

In Method E, an aryl amine bearing R₃ (IX) is dissolved in aconcentrated aqueous acid such as hydrochloric, hydrobromic or sulfuricand cooled to ice bath temperatures. The most preferred acid ishydrochloric with concentrations between 3-8 N with the most preferredconcentration of 6 N. A nitrosating reagent in water is added dropwisewhile maintaining a cold temperature. The preferred temperature is ₀-5°C. The preferred reagent is sodium nitrite. The reaction is stirredbetween 10-90 min and a reducing agent is added while maintaing coldtemperatures. The preferred temperature is 0-5° C. Reducing agentsinclude zinc, iron, samarium iodide and tin(II) chloride. The mostpreferred agent is tin(II) chloride dissolved in aqueous hydrochloricacid with a concentration of 3-8 N with a most preferred concentrationof 6 N. The reaction is stirred between 0.5-3 hand quenched with alkalito a pH between 12-14. Alkali reagents include sodium hydroxide,potassium hydroxide, lithium hydroxide and calcium hydroxide. The mostpreferred alkali reagent is potassium hydroxide. The aqueous solution isextracted with a non-protic organic solvent, such as diethyl ether,chloroform, ethyl acetate and methylene chloride. The organic layers aredried with agents such as MgSO₄ and Na₂SO₄ and the volatiles removed toprovide the aryl hydrazine (X), which can be carried forward withoutfurther purification.

A β-ketonitrile bearing R₁ (XIV) may be prepared by Method F or G. InMethod F, a metal hydride, such as sodium hydride, potassium hydride orlithium hydride, is suspended in an anhydrous, inert, non-proticsolvent, such as diethyl ether, THF and dioxane, at temperatures between35-85° C. The most preferred metal hydride is sodium hydride and themost preferred solvent is THF at a temperature of 75° C. An alkyl ester,preferably a methyl ester (XI), and acetonitrile is dissolved in ananhydrous, inert, non-protic solvent, such as diethyl ether, THF ordioxane and added dropwise to the metal hydride suspension. Thepreferred solvent is THF. The mixture is kept at elevated temperaturesbetween 3-24 h, cooled to room temperature and diluted with a non-proticsolvent and aqueous acid. The organic layer is washed with water andbrine, dried, with agents such as MgSO₄ and Na₂SO₄, and the volatilesremoved to provide the β-ketonitrile (XIV), which could be used withoutfurther purification.

Alternatively, following Method G, a solution of a strong base, such asalkyl lithium reagents and metal amide reagents, such as n-butyllithium, sec-butyl lithium, methyl lithium and lithium diisopropylamide,in an anhydrous, inert, non-protic solvent, such as diethyl ether, THFand dioxane, is cooled below 0° C. The preferred base is n-butyllithium, the preferred solvent is THF and the preferred temperature is−77° C. A solution of cyanoacetic acid (XII) in an anhydrous, inert,non-protic solvent, such as diethyl ether, THF and dioxane, and mostpreferrably THF, is added dropwise while maintaining a reactiontemperature below 0° C. and preferrably at −77° C. The reaction isstirred between 10-45 min while warming to 0° C. The solution of thedianion of cyanoacetic acid is cooled to temperatures below −25° C. andpreferrably at −77 C. An alkyl acid chloride (XIII) dissolved in ananhydrous, inert, non-protic solvent, such as diethyl ether, THF anddioxane, and most preferrably THF, is added. The reaction mixture iswarmed to 0° C. betweeen 10-30 min and quenched with aqueous acid. Theproduct is extracted with an organic solvent, such as chloroform, ethylacetate, ether and methylene chloride. The combined organic extracts aredried, with agents such as MgSO₄ and Na₂SO₄, and the volatiles removedto provide the β-ketonitrile (XIV), which could be used without furtherpurification.

The desired aminopyrazole (XV) may then be prepared by Method H or I. InMethod H, aryl hydrazine X and β-ketonitrile XIV are mixed in an organicsolvent, such as toluene, ethanol, iso-propanol or t-butanol. Thepreferred solvent is ethanol. An acid, such as hydrochloric acid,p-toluene sulfonic acid or sulfuric acid, is added, The preferred acidis concentrated hydrochloric acid. The mixture is heated to temperaturesbetween 50-1000° C., preferably at 80° C., for 10-24 h and cooled toroom temperature. The mixture is diluted with non-protic organicsolvent, such as ethyl acetate, ether, chloroform and methylenechloride, and washed with aqueous alkali, such as sodium bicarbonate andpotassium carbonate. The organic layer is dried, with agents such asMgSO₄ and Na₂SO₄, and the volatiles removed to provide a residue whichis purified by recrystallization or silica gel chromatography usinghexanes and ethyl acetate as eluents. The product-rich fractions arecollected and the volatiles removed to provide the desired aminopyrazole(XV).

Alternatively, using Method I, aryl hydrazine X and β-ketonitrile XIVare mixed in an organic solvent, such as toluene, ethanol, iso-propanolor t-butanol. The preferred solvent is toluene. The mixture is heated atreflux temperatures for 3-24 h with azeotropic removal of water andworked up as described above providing the amidopyrazole XV.

The synthesis of other desired aminoheterocycles that may be used inpreparation of compounds of formula I or Ia can be prepared by methodsknown in the art and described in the literature. The examples thatfollow in Schemes III-XV are illustrative and, as recognized by oneskilled in the art, particular reagents or conditions could be modifiedas needed for individual compounds. Intermediates used in the schemesbelow are either commercially available or easily prepared fromcommercially available materials by those skilled in the art.

A general synthesis for desired aminothiophenes is illustrated in SchemeIII, Method J.

A mixture of 1-aryl-5-alkyl-butane-1,4-dione (XVI) and a sulfatingreagent, such as Lawesson's reagent or phosphorous (V) sulfide,preferably Lawesson's reagent, is dissolved in a non-protic, anhydroussolvent, such as toluene, THF and dioxane. The preferred solvent istoluene. The mixture is heated at elevated temperatures and preferablyat a solvent-refluxing temperature for 1-10 hr. The volatiles areremoved and the residue is purified by silica gel chromatography usinghexanes and ethyl acetate as eluent. The product-rich fractions arecollected and the volatiles removed to provide the substituted thiopheneXVII.

A mixture of substituted thiophene XVII is dissolved in a solvent suchas acetic anhydride or acetic acid. The preferred solvent is aceticanhydride. The mixture is cooled to 0-30° C. and preferrably to −10° C.A solution of concentrated nitric acid in a solvent such as aceticanhydride or acetic acid, with the preferred solvent being aceticanhydride is added while cooling to 0-30° C. and preferably to −10° C.The mixture is stirred between 10-120 min, poured onto ice and extractedwith a non-protic solvent such as diethyl ether, chloroform, ethylacetate or methylene chloride. The organic 15 extracts are washed withaqueous alkali, dried with agents such as MgSO₄ and Na₂SO₄ and thevolatiles removed. The residue is purified by silica gel chromatographyusing hexanes and ethyl acetate as eluents. The product-rich fractionsare collected and the volatiles removed to provide the2-aryl-5-alkyl-3-nitrothiophene. The 2-aryl-5-alkyl-3-nitrothiophene isreduced by metals, such as iron, tin and zinc or catalytichydrogenation. The preferred reduction conditions are iron in aceticacid at temperatures between 50-110° C. and preferrably at 100° C. for5-30 min. After cooling to room temperature the reaction is diluted withwater, neutralized with alkali, such as sodium hydroxide, potassiumhydroxide, potassium carbonate or sodium bicarbonate, and extracted witha non-protic solvent such as diethyl ether, ethyl acetate or methylenechloride. The organic extracts are dried with agents such as MgSO₄ andNa₂SO₄ and the volatiles removed to provide the desired aminothiopheneXVIII.

Scheme IV outlines a general scheme for desired aminofurans as describedby Stevenson et al. (J. Am. Chem. Soc., 1937, 59, 2525). An ethylaroylacetate (XIX) is dissolved in a non-protic solvent, such as etheror THF, and treated with a strong base, such as sodium, sodium ethoxideor sodium hydride, and the anion is reacted with a bromomethylalkylketone (XX) at low temperatures, such as 0° C. After stirring thereaction until no starting material remains, it is poured onto coldwater and extracted with a non-protic solvent. The combined extracts aredried with agents such as MgSO₄ or Na₂SO₄. The diketo-ester (XXI) may becarried forward without further purification or purified by distillationor silica gel chromatography. The diketo-ester in a protic solvent, suchas ethanol, is heated in the presence of a mineral acid, such assulfuric or hydrochloric, for 5-10 h and extracted with a non-proticsolvent. The combined extracts are dried with agents such as MgSO₄ orNa₂SO₄. The furan-ester (XXII) may be carried forward without furtherpurification or purified by distillation or silica gel chromatography.The furan-ester in a protic solvent, such as ethanol, is treated withhydrazine hydrate and the mixture heated for 2-5 days. The hydrazide isisolated as above and treated with hot formic acid and the resultingfuran-amine (XXIII) purified by distillation or silica gelchromatography.

The synthesis of substituted 4-aminooxazoles may be achieved analogousto a procedure described by Lakhan et al. (J. Het. Chem., 1988, 25,1413) and illustrated in Scheme V. A mixture of aroyl cyanide (XXIV),aldehyde (XXV) and anhydrous ammonium acetate in acetic acid is heatedat 100-110° C. for 3-6 hr, cooled to room temperature and quenched withwater. Extraction by a non-protic solvent provides the product XXVIwhich can be carried forward without further purification or purified byrecrystallization or silica gel chromatography.

The synthesis of substituted 3-aminopyrroles (XXX) may be achieved in amanner analogous to Aiello et al., J Chem. Soc. Perkins Trans. I,1981, 1. This is outlined in Scheme VI. A mixture of aryldioxoalkane(XXVII) and amine (XXVIII) in acetic acid is heated at 100-110° C. for3-6 h and worked up in the usual manner. The product (XXIX) in aceticacid is treated with a nitrating agent, such as nitric acid andpotassium nitrate in concentrated sulfuric acid. The mixture is pouredonto cold water and extracted with a non-protic solvent. The combinedextracts are dried with agents such as MgSO₄ and Na₂SO₄. Removal of thevolatiles provides the nitro-pyrrole which which may be carried forwardwithout further purification or purified by recrystallization or silicagel chromatography. The nitro-pyrrole is reduced to the amine with ironin acetic acid or by catalytic hydrogenation using palladium onactivated carbon. The aminopyrrole (XXX) may be carried forward withoutfurther purification or purified by recrystallization or silica gelchromatography.

In an analogous fashion, a mixture of amine XXXI and3-aryl-2,5-dioxoalkane (XXXII) in acetic acid is heated between 80-110°C. for 2-24 hr. The reaction is diluted with water and extracted with anorganic solvent. The combined extracts are dried with agents such asMgSO₄ or Na₂SO₄ and the volatiles removed. The resulting pyrrole istreated with a nitrating agent and subsequently reduced to XXXIII asdescribed above. The product may be carried forward without furtherpurification or purified by recrystallization or silica gelchromatography. This process is illustrated in Scheme VII.

Substituted 5-aminothiazoles (XXXVII) may be prepared in a manneranalogous to Gerwald et al., J Prakt. Chem. 1973, 315, 539. Asillustrated in Scheme VIII, to a mixture of aminocyanide XXXIV, aldehydeXXXV and sulfur in an anhydrous solvent, such as ethanol and methanol,is added dropwise a base, such as triethylamine. The mixture is heatedat 50° C. for 1-3 hr. The mixture is cooled and the excess sulfurremoved. Acetic acid is added to neutralize the mixture and the solidcollected. The imine XXXVI is treated with acid, such as hydrochloricand toluenesulfonic acid, in water and an organic solvent. After thestarting material is consumed the reaction is worked up and the productXXXVII may be carried forward without further purification or purifiedby recrystallization or silica gel chromatography.

A synthesis of substituted 2-aminothiophenes (XXXIX), analogous to aprocedure described by Gewald et al. (J. Prakt. Chem., 1973, 315, 539)is illustrated in Scheme IX. A mixture of disubstitutedthiophene-3-carboxylic acid (XXXVJII) in a protic solvent, such asacetic acid, at a temperature of 0-50° C. is treated with a nitratingagent, such as nitric acid or potassium nitrate in concentrated sulfuricacid. After the starting material has been consumed the reaction ispoured onto ice and the product extracted with a non-protic solvent. Thecombined extracts are dried with agents such as MgSO₄ and Na₂SO₄ and thevolatiles removed. The nitrothiophene is reduced to the amine with ironin acetic acid or by catalytic hydrogenation using palladium onactivated carbon. The amino-thiophene may be carried forward withoutfurther purification or purified by recrystallization or silica gelchromatography.

1,5-Disubstituted-3-aminopyrazoles (XLII) may be prepared as shown inScheme X, in a fashion analogous to the procedure described by Ege etal. (J. Het. Chem., 1982, 19, 1267). Potassium is added to anhydroust-butanol and the mixture cooled to 5° C. Hydrazine XL is added,followed by cyanodibromoalkane XLI. The mixture is heated at refluxingtemperatures for 3-10 hr. The mixture is cooled to room temperature andpoured onto ice water. The product is extracted with an organic solvent.The combined extracts are dried with agents such as MgSO₄ or Na₂SO₄ andthe volatiles removed. The product XLII may be carried forward withoutfurther purification or purified by recrystallization or silica gelchromatography.

The synthesis of 2-amino-3,5-disubstituted thiophenes shown in SchemeXI, is done in a fashion analogous to Knoll et al., J Prakt. Chem.,1985, 327, 463. A mixture of substitutedN-(3-aminothioacryloyl)-formamidine (XLIII) and substituted bromide(XLIV) in a protic solvent, such as methanol or ethanol, is heated,preferably at a reflux temperature, for 5-30 min and cooled below roomtemperature. The product thiophene-imine is filtered and dried. Thethiophene-imine XLV is converted to the thiophene-amine (XLVI) bytreatment with aqueous acid.

The synthesis of 1,4-disubstituted-2-aminopyrroles (L) may beaccomplished in a manner analogous to Brodrick et al. (J. Chem. Soc.Perkin Trans. I, 1975, 1910), and as illustrated in Scheme XII. Thepotassium salt of formylnitrile XLVII in water is treated with amineXLVIII and acetic acid and the mixture heated at 50-90° C. for 5-30 min.The aminonitrile XLIX is collected by filtration upon cooling and thenis stirred at room temperature with a base such as ethanolic potassiumethoxide for 2-5 h and the volatiles removed. The residue is dilutedwith water and extracted with an organic solvent. The combined extractsare dried with agents such as MgSO₄ and Na₂SO₄ and the volatilesremoved. The product (L) may be carried forward without furtherpurification or purified by recrystallization or silica gelchromatography.

The preparation of 1,2-disubstituted-4-aminoimidazoles (LII) byreduction of the corresponding nitro compound (LI), for example withiron in acetic acid or catalytic hydrogenation may be accomplished asdescribed by Al-Shaar et al. (J. Chem. Soc. Perkin Trans. I, 1992, 2779)and illustrated in Scheme XIII.

2,4-Disubstituted 5-aminooxazoles (LVII) may be prepared in a manneranalogous to the procedure described by Poupaert et al. (Synthesis,1972, 622) and illustrated in Scheme XIV. Acid chloride LIII is added toa cold mixture of 2-aminonitrile LIV and a base such as triethylamine ina non-protic solvent, such as THF, benzene, toluene or ether. Thepreferred temperature is ₀° C. The mixture is stirred for 12-24 h andwashed with water. The volatiles are removed and the product LV treatedwith ethylmercaptan and dry hydrogen chloride in dry methylene chloridefor 5-30 min. The solid 5-imino-1,3-oxazole hydrochloride (LVI) iscollected by filtration, dissolved in dry pyridine and the solutionsaturated with hydrogen sulfide during 4 h at 0° C. The mixture isdiluted with an organic solvent and washed with water and dried. Removalof the volatiles provides the 5-amino-1,3-oxazole product (LVII) whichmay be carried forward without further purification or be purified bysilica gel chromatography.

The synthesis of 1,4-disubstituted-2-aminopyrazoles may be accomplishedas illustrated in Scheme XV and described in Lancini et al., J. Het.Chem., 1966, 3, 152. To a mixture of substituted aminoketone (LVIII) andcyanamide in water and acetic acid was added aqueous sodium hydroxideuntil pH 4.5 is reached. The mixture is heated at 50-90° C. for 1-5 hr,cooled and basicified with ammonium hydroxide. The product LIX iscollected by filtration and dried.

Aryl amine and heteroaryl amine intermediates IV (G-NH₂) for thesynthesis of compounds of formulas II and III are either commerciallyavailable or easily prepared by methods known to those skilled in theart. For example, one may obtain desired aryl amines and heteroarylamines by nitration and reduction of a substituted aryl or heteroarylring as illustrated in the synthesis of several 5-membered heterocycleamines (Ar₁—NH₂) in the above schemes. Alternatively, one may convert asubstituted aryl ester to an aryl amine as illustrated for thesubstituted faran in Scheme IV above, and exemplified in syntheticexample 17 below. Several additional syntheses of G-NH₂ and Ar₁—NH₂ areprovided in the Synthetic Examples section.

Methods by which intermediates V and VI (Scheme I, D′=Ar—X—Y—Z orAr₂—X—Y—Z) may be prepared are described below. In Method K (SchemeXVI), a bromoarylamine LX, which may be commercially available or easilyprepared by one skilled in the art, is reacted with a cycloalkenone LXIin the presence of a transition metal catalyst, for example apalladium(II) catalyst such as bis(triphenylphosphine)palladium(II)chloride, in the presence of a bis(triphenylphosphine) chelator, such as

1,2-bis(diphenylphosphino)ethane (DPPE),1,1′-bis(diphenylphosphino)ferrocene (DPPF) and1,3-bis(diphenylphosphino)propane (DPPP), preferably DPPP, and a base,preferably sodium bicarbonate, in a suitable solvent, preferably DMF ata temperature of about 150° C. to provide LXII. LXII may then be used(as VI) in Method B (Scheme I), or converted to isocyanate LXIII byreaction with phosgene or a phosgene equivalent in the presence of abase, such as sodium bicarbonate in a suitable solvent such asdichloromethane, at a temperature of about 0° C., and used (as V) inMethod A. The resulting product LXIV may be modified further by methodsknown by one skilled in the art to obtain desired compounds of formulaI, as described in synthetic examples below.

In Method L, bromide LXV is reacted with a strong base, such as t-butyllithium, in a suitable solvent, such as THF, with tributyltin chlorideat a temperature of about −50° C. to −100° C., preferably about −78° C.to give LXVI. LXVI is then reacted with LX in a suitable solvent, suchas THF or 1,4-dioxane, in the presence of a transition metal catalyst,preferably tetrakis(triphenylphosphine)palladium(0), at a temperature ofabout 50° C. to 150° C., preferably about 100° C. and in a sealed tube,providing LXVII. LXVII may then be used (as VI) in Method B or C (SchemeI), or converted to the corresponding isocyanate as described in MethodK, and used (as V) in Method A.

Methods by which Y and Z may be joined to X are illustrated in SchemeXVII. As illustrated by Method M, if one desires a product in which Yincludes an amino nitrogen bonded to X, an X containing a ketone may bereacted with a Y—Z containing a terminal primary or secondary amineunder reductive amination conditions. For example, ketone LXIV iscombined with a primary or secondary amine, in a suitable solvent suchas THF. An acid, such as acetic acid, is added, followed by a suitablereducing agent, preferably sodium cyanoborohydride or sodium(triacetoxy)borohydride, to provide the desired product LXVIII.

Method N, illustrates a procedure for obtaining a methylene group for Yand a primary or secondary amine for Z. An X group bearing an aldehydeand a halogen, preferably bromine (LXIX), may be reacted with a primaryor secondary amine under reductive amination conditions as described inMethod M to provide LXX. This intermediate may then be used as describedin Method L.

As in the cases described above, the synthesis of additionalintermediates corresponding to V, VI and VII may be accomplished bymethods similar to those described in the literature or known to thoseskilled in the art. Several examples are provided in the SyntheticExamples section below.

SYNTHETIC EXAMPLES Example 11-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-cyclohexenon-3-yl)naphthalen-1-yl]urea

As outlined in Method K, a 350 mL sealed tube under inert atmosphere wascharged with 4-bromo-1-naphthylamine (LXXI) (1.97 g; 8.9 mmol; 1equiv.), 2-cyclohexenone (1.65 g; 17.2 mmol; 1.9 equiv.), sodiumbicarbonate powder (2.17 g; 25.8 mmol; 2.9 equiv.),1,3-bis(diphenylphosphino)propane (177 mg; 0.43 mmol; 0.05 equiv.),bis(triphenylphosphine)palladium(II) chloride (302 mg; 0.43 mmol; 0.05equiv.) and DMF (degassed, 100 mL). The mixture was heated at 150° C.for 8 h. After cooling back to ambient temperature, the mixture wasdiluted with 100 mL EtOAc and filtered through diatomaceous earth. Thesolution was then transferred to a separatory funnel and washed withwater (100 mL) and saturated brine (100 mL). After drying with MgSO₄ thevolatiles were removed in vacuo. The product was then purified by columnchromatography using EtOAc (10 to 50%) in hexanes as eluent to provide1.3 g material which was recrystallized from hot EtOAc/Hexanes to afford800 mg LXXII (3.4 mmol; 38% yield) as a dark brown solid. LXXII (100 mg;0.42 mmol; 1 equiv.) was dissolved in methylene chloride (20 mL) andsaturated aqueous sodium bicarbonate (20 mL) was added. The mixture wasvigorously stirred at 0° C. for 15 min. The stirring was then stoppedand phosgene (˜2.0 M in toluene; 0.63 mL; 1.26 mmol; 3.0 equiv.) wasadded via syringe to the organic layer in one portion. Stirring wasimmediately resumed and continued at 0° C. for 20 min. The layers werethen separated and the aqueous phase was extracted further withmethylene chloride (1×25 mL). The combined organics were dried (Na₂SO₄),filtered and ¾ of the solvent removed in vacuo. This solution ofisocyanate LXXIII was then immediately diluted with anhydrous THF (8 mL)and treated with LXXIV at room temperature (Method A). The mixture wasleft stirring under nitrogen overnight then MeOH (2 mL) was added andthe volatiles removed in vacuo. The title compound 1 was thus obtainedas an orange/red foam (200 mg; 0.41 mmol; 74%). This was recrystallizedovernight from EtOAc twice to afford 49 mg of yellow crystals (mp:168-170° C.).

Example 21-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-{4-[3-(morpholin-4-yl)cyclohexen-1-yl]naphthalen-1-yl}urea

As described in Method M, the product from Example 1 (1) (93 mg; 0.19mmol; 1 equiv.) and morpholine (30 uL; 0.34 mmol; 1.8 equiv.) weredissolved in 1.0 mL anhydrous THF and treated with acetic acid (16 uL;0.28 mmol; 1.5 equiv.) and sodium (triacetoxy)borohydride (80 mg; 0.39mmol; 2 equiv.). The reaction was stirred at room temperature for 2days, then 5% aqueous NaOH solution (3 mL) was added and the reactionthen extracted with EtOAc (3×3 mL). The combined organics were washedonce with water, then brine, dried (Na₂SO₄), filtered and the solventsremoved in vacuo. Column chromatography using EtOAc/hexanes as eluentafforded 64 mg of a tan foam (0.11 mmol; 60%). This was chromatographeda second time with 5% MeOH in methylene chloride to provide the titlecompound 2 as a light purple foam (50 mg).

Example 31-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-{4-[5-(morpholin-4-ylmethyl)fur-2-yl]naphthalen-1-yl}urea:

As described in Method N, to a mixture of 5-bromo-2-furaldehyde (LXXV)(1.76 g) and morpholine (1.00 ml) in 40 mL anhydrous THF at roomtemperature was added acetic acid (0.60 mL) followed by sodiumtriacetoxyborohydride (3.28 g). The mixture was stirred at roomtemperature for 3 h and then poured into a saturated solution of sodiumbicarbonate (100 mL). After stirring vigorously for 5 min the layerswere separated and the aqueous layer was extracted with EtOAc. Thecombined organic layers were washed with brine, dried (Na₂SO₄), filteredand evaporated to dryness. Purification of the residue by flashchromatography afforded 2.09 g (8.49 mmol, 84% yield) of LXXVI.

As illustrated by Method L, LXXVI (0.678 g, 2.76 mmol) was dissolved in10 mL anhydrous THF under inert gas atmosphere and the solution wascooled to at −78° C. t-Butyllithium (4.0 mL of a 1.7 M solution inpentane) was added dropwise and the solution was stirred at −78° C. for30 min. Tributyltinchloride (0.60 mL, 0.72 g, 2.2 mmol) was added andthe solution was stirred for another 30 min at −78° C. pH7 Buffer(NaH₂PO₄/Na₂HPO₄ sat.) was added (10 mL) and the mixture was warmed toroom temperature. The layers were separated and the aqueous layer wasextracted with EtOAc. The combined organic layers were washed withbrine, dried (Na₂SO₄), filtered and evaporated to dryness. Purificationof the residue by flash chromatography afforded 0.526 g (1.15 mmol, 42%yield) of LXXVII.

As outlined in Method L, LXXVII (0.399 g, 0.874 mmol) and LXXI (0.200 g,0.901 mmol) were dissolved in 10 mL anhydrous 1,4-dioxane in a sealabletube under inert gas atmosphere. The solution was degassed and purgedwith nitrogen (2×). Tetrakis(triphenylphosphine)palladium(0) (0.057 g,0.049 mmol) was added and the solution was degassed and purged withnitrogen again (2×). The tube was sealed and heated to 100° C. for 24 h.After cooling to room temperature the mixture was diluted with EtOAc,saturated aqueous potassium carbonate solution (10 mL) was added and themixture was stirred for 1 h at room temperature. The mixture wasfiltered over diatomaceous earth and the layers were separated. Theaqueous layer was extracted with EtOAc. The combined organic layers werewashed with brine, dried (Na₂SO₄), filtered an evaporated to dryness.Purification of the residue by flash chromatography afforded 0.314 g ofa yellow oil, which contained LXXVIII along with tributyltin bromide.This mixture was used for the next step without further purification.LXXVIII (0.283 g, 0.917 mmol) was reacted with the phenylcarbamate ofLXXIV (0.395 g, 1.13 mmol) according to Method C. The product waspurified by flash chromatography to give the title compound 3 as ayellow solid (0.338 g, 0.600 mmol, 65% yield) that was further purifiedby recrystallization to give 0.131 g of title compound 3 (mp. 144-146°C.).

Example 41-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-{4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl}urea:

As described by R. J. Chambers and A. Marfat, (Synthetic Communications,1997, 27, 515) a mixture of 2,5-dibromopyridine (LXXIX) (9.90 g, 41.78mmol), Pd(dppf)Cl₂(1.51 g, 1.85 mmol), anhydrous MeOH (40 mL), anhydrousDMF (40 mL) and anhydrous triethylamine (12 mL) was purged in a Parrapparatus with a stream of carbon monoxide for 10 min and then stirredunder 80 psi carbon monoxide at 50° C. for 4 h. The mixture was dilutedwith EtOAc (600 mL) and washed with water (2×100 mL) and brine (1×100mL), dried (sodium sulfate), filtered and evaporated to dryness. Theresidue was purified by flash chromatography on silica gel (40% EtOAc inhexanes) to give LXXX as a light orange solid (3.733 g, 17.28 mmol,41%).

To a solution of compound LXXX (165.9 mg, 0.7679 mmol) in anhydrous THF(10 mL) at −78° C. was added dropwise diisobutylaluminum hydride (1.0 Min THF) (2.0 mL, 2.0 mmol). The mixture was stirred at −78° C. for 2 h,then saturated potassium carbonate (0.6 mL) solution was added, themixture was warmed to room temperature and stirred for another 30 min.Sodium sulfate was added and the mixture was stirred for 10 min. Thesolids were removed by filtration and the filtrate was evaporated todryness. The residue was purified by flash chromatography on silica gel(20% EtOAc in hexanes) to give aldehyde LXXXI as a white solid (80 mg,0.43 mmol, 56%).

To a solution of LXXXI (367.7 mg, 2.0 mmol) in anhydrous1,2-dichloroethane (10 mL) was added morpholine (0.20 mL, 0.20 g, 2.3mmol), followed by glacial acetic acid (0.12 mL, 0.13 g, 2.1 mmol) andsodium triacetoxyborohydride (625 mg, 2.95 mmol). The mixture wasstirred at room temperature for 30 min. A saturated solution of sodiumbicarbonate (10 mL) was added and the mixture was stirred vigorously foranother 30 min. The layers were separated and the aqueous layer wasextracted with EtOAc (3×20 mL). The combined organic layers were washedwith brine, dried (sodium sulfate), filtered and evaporated to dryness.Flash chromatography (1% triethylamine in EtOAc) of the residue gaveLXXXII as a light yellow oil (460.8 mg, 1.79 mmol, 91%).

To a solution of tert-butyllithium (1.42 M in pentane) (2.80 mL, 3.98mmol) in anhydrous THF (20 mL) at −78° C. was added dropwise a solutionof LXXXII (460.8 mg, 1.792 mmol) in anhydrous THF (10 mL) and themixture was stirred at −78° C. for 10 min. Tributyltin chloride (0.49mL, 0.59 g, 1.8 mmol) was added and the mixture was stirred at −78° C.for another 15 min. pH 7 Buffer (Na₂HPO₄/NaH₂PO₄ sat.) (10 mL) was addedand the mixture was warmed to room temperature. The layers wereseparated and the aqueous layer was extracted with EtOAc (3×20 mL). Thecombined organic layers were washed with brine, dried (sodium sulfate),filtered and evaporated to dryness. Flash chromatography (EtOAc) of theresidue gave LXXXIII as colorless oil (548.8 mg, 1.17 mmol, 65%).

A degassed solution of LXXXIII (302 mg, 0.646 mmol), LXXI (177 mg, 0.797mmol) and Pd(PPh₃)₄ (55 mg, 0.48 mmol) in anhydrous 1,4-dioxane (10 mL)was heated to 100° C. in a sealed tube for 16 h. The black precipitatewas removed by filtration and the tube was washed with EtOAc. Thecombined filtrates were stirred with potassium fluoride solution (40%)(10 mL) for 30 min. Water and brine were added, the layers wereseparated and the aqueous layer was extracted with EtOAc (4×50 mL). Thecombined organic layers were washed with brine, dried (sodium sulfate),filtered and evaporated to dryness. Flash chromatography (5% MeOH and 1%triethylamine in EtOAc) of the residue gave LXXXIV as a light brownsolid (157.6 mg, 0.49 mmol, 76%).

LXXXIV and the phenyl carbamate of LXIV were reacted according to MethodC. Purification by flash chromatography using 5% MeOH and 1%triethylamine in EtOAc as the eluent followed by recrystallization fromEtOAc/hexanes gave the title compound 4 as a white solid (mp. 169-170°C.).

Example 51-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-{4-[3-(morpholin-4-yl)phenyl]naphthalen-1-yl}urea

3-Bromoaniline (3.0 mL, 4.7 g, 28 mmol), 2-bromoethylether (4.2 mL, 7.7g, 33 mmol) and diisopropylethylamine (15 mL, 11 g, 86 mmol) weredissolved in anhydrous DMF (20 mL) under inert gas atmosphere and heatedto 100° C. for 6 h. After cooling to room 5 temperature the mixture waspoured into water (300 mL) and extracted with EtOAc. The combinedorganic layers were washed with brine, dried (Na₂SO₄), filtered andevaporated to dryness. Purification of the residue by flashchromatography afforded 2.9 g (12 mmol, 43% yield) of LXXXVI

LXXXVI (1.73 g, 7.13 mmol) was dissolved in anhydrous THF (30 mL) andcooled to −78° C. t-Butyllithium (10.0 mL of a 1.7 M solution inpentane) was added dropwise and the solution was stirred at −78° C. for30 min. Tributyltinchloride (1.90 mL, 2.28 g, 7.00 mmol) was added andthe solution was stirred for another 45 min at −78° C. pH 7 Buffer(NaH₂PO₄/Na₂HPO₄ sat.) was added (10 mL) and the mixture was warmed toroom temperature. The layers were separated and the aqueous layer wasextracted with EtOAc. The combined organic layers were washed withbrine, dried (Na₂SO₄), filtered an evaporated to dryness. Purificationof the residue by flash chromatography afforded 2.28 g (5.36 mmol, 77%yield) of LXXXVII.

LXXXVII (1.49 g, 3.51 mmol) and LXXI (0.69 g, 3.11 mmol) were dissolvedin 20 mL anhydrous 1,4-dioxane in a sealable tube under inert gasatmosphere. The solution was degased and purged with nitrogen (2×).Tetrakis(triphenylphosphine)palladium(0) (0.21 g, 0.18 mmol) was addedand the solution was degassed and purged with nitrogen again (2×). Thetube was sealed and heated to 100° C. for 17 h. After cooling to roomtemperature the mixture was diluted with EtOAc, saturated aqueouspotassium carbonate solution (10 mL) was added and the mixture wasstirred for 1 h at room temperature. The mixture was filtered overdiatomaceous earth and the layers were separated. The aqueous layer wasextracted with EtOAc. The combined organic layers were washed withbrine, dried (Na₂SO₄), filtered and evaporated to dryness. Purificationof the residue by flash chromatography afforded 0.363 g (1.19 mmol, 38%)of LXXXVIII.

LXXXVIII (0.360 g, 1.18 mmol) was reacted with the phenylcarbamate ofLXIV (0.69 g, 1.97 mmol) according to Method C. The product was purifiedby flash chromatography to give a colorless solid (0.433 g, 0.77 mmol,66% yield) that was further purified by recrystallization fromEtOAc—hexanes to give 0.344 g of the title compound 5 (mp. 188-190° C).

Table 1 illustrates additional compounds of the invention, which wereprepared by methods analogous to those described above.

TABLE 1

Ex. No. R₁ R₃ X^(a) Y^(b) Z^(c) m.p. ° C. 6 t-Bu 4-MePh Phenyl 4-CH₂4-morpholinyl 146-148 7 t-Bu 4-MePh Phenyl 3-CH₂ 4-morpholinyl 120-122 8t-Bu 4-MePh Phenyl Bond 4^(d)-(4-morpholinyl) >230 9 t-Bu 4-MePh Phenyl4-CH₂ 4-morpholinyl 183-186 10 t-Bu 4-MePh Phenyl 4-CH₂ NMe₂ 108-114 11t-Bu 4-MePh 2-pyridyl 5-CH₂ 4-morpholinyl foam 12 t-Bu 4-MePh1-cycloheptenyl Bond 3^(d)-(4-morpholinyl) 133-135 13 t-Bu6-Me-3-pyridyl 3-pyridyl 6-(CH₂) 4-morpholinyl 162-165 14 t-Bu Me3-pyridyl 6-(CH₂) 4-morpholinyl foam 15 t-Bu 6-Me-3-pyridyl1-cyclohexenyl 3-[NH—(CH₂)₂] 4-morpholinyl ^(a)number refers to positionon X that is bonded to naphthalene ring (Ar₂). ^(b)number refers toposition on X that Y is bonded to. ^(c)number refers to position on Zthat is bonded to Y (or X if Y is a bond). ^(d)refers to position on Xthat Z is bonded to.

Example 161-[4-(6-{[Bis-(2-cyanoethyl)amino]methyl}pyridin-3-yl)naphthalen-1-yl]-3-(5-tert-butyl-2-methylphenyl)urea

To a solution of 4-tert-butyl toluene (33.7 mmol) in acetonitrile (150mL) at 0° C. was added nitronium tetrafluoroborate (40.5 mmol). After 30min at room temperature, the reaction was diluted with water (50 mL) andextracted with EtOAc (3×30 mL). The combined organic extracts werewashed with brine and dried (MgSO₄). Removal of the volatiles in vacuoleft a residue; flash chromatography using 10% methylenechloride/petroleum ether as eluent provided 4-tert-butyl-2-nitrotoluene.

4-tert-Butyl-2-nitrotoluene (1.1 mmol) was dissolved in DMF (10 mL). Thecatalyst (10% Pd/C, 5 mg) was added followed by the addition ofdi-tert-butyl dicarbonate (1.4 mmol). The system was purged with argonthen exposed to H₂ (1 atm) for 12 h. The mixture was filtered over a padof diatomaceous earth; the filtrate was diluted with water and extractedwith EtOAc (3×10 mL). The combined organic extracts were washed withbrine and dried (MgSO₄). N-Boc-5-tert-butyl-2-methylaniline was obtainedas a crystalline solid, 265 mg, after the evaporation of volatiles.

To a mixture of N-boc-5-tert-butyl-2-methylaniline (0.8 mmol) andtriethylamine (0.22 mol) in benzene (10 mL) at room temperature wasadded via syringe boron trichloride (0.4 mmol). The resultingheterogenous mixture was stirred at 80 C. for 30 min. The heat sourcewas removed, and aminonaphthalene LXXXIX was added (0.7 mmol). Thereaction mixture was stirred at room temperature for 16 h. The reactionmixture was diluted with water (10 mL) and extracted with EtOAc (3×10mL). The combined organic extracts were washed with brine and dried(MgSO₄). Removal of the volatiles in vacuo left a residue; flashchromatography using 10% MeOH/EtOAc as eluent provided 300 mg of thedesired urea XC.

This urea was subjected to acidic conditions to remove the acetal whichexposed the aldehyde functionality. In 1,2-dichloroethane, 1.25equivalents of bis(2-cyanoethyl)amine were added to this aldehydefollowed by the addition of sodium triacetoxyborohydride (1.5equivalents). After column chromatography (5% MeOH/EtOAc), the titlecompound 16 was obtained.

Example 171-(6-tert-Butyl-2-chloro-3-methylpyridin-4-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]urea

To a stirred solution of N-Boc-1-amino-4-bromo naphthalene (15.5 mmol)in anhydrous THF (40 mL) at −78° C. was added n-BuLi (47 mmol). Theresultant yellow-green solution was stirred at −78° C for two h then wastransferred to a solution of trimethylborate (5.64 grams, 54.2 mmol) inanhydrous THF (25 mL) at −42° C. The reaction was allowed to warm toroom temperature overnight as the bath warmed. After stirring for 16 h,5% aqueous HCl was added (25 mL) and the mixture was stirred for 15 min.The aqueous layer was saturated with NaCl and the layers were separated.The aqueous portion was extracted with diethyl ether (3×60 mL) and thecombined organics were extracted with 0.5 M NaOH (6×30 mL). The combinedbasic extracts were acidified to ˜pH 2 with 3 M HCl (˜30 mL) and thesuspension was extracted with diethyl ether (3×100 mL). The combinedethereal extracts were dried (MgSO4), filtered and the solvent wasremoved to afford the boronic acid XCI as a beige solid (2.3 g) whichwas used without further purification.

5-Bromo-2-(morpholin-4-ylmethyl)pyridine (0.70 mmol) and XCI (0.70 mmol)were dissolved in a biphasic mixture of dimethoxyethane (2 mL) and 2 Maq. Na₂CO₃ (1 mL). The reaction was purged with a stream of N₂ for 15min, the Pd catalyst was added, and the mixture was heated at 85° C. for16 h. The reaction was cooled to room temperature and was partitionedbetween water (10 mL) and EtOAc (75 mL). The layers were separated andthe organic portion was washed with brine (20 mL), dried (MgSO4),filtered and the solvent was removed to afford a brown solid. Columnchromatography afforded the product XCII as a beige solid.

XCII (0.50 mmol) was dissolved in 2 mL anhydrous dioxane and HCl wasadded (2.5 mmol). The solution was stirred at room temperature for 16 h.To the resultant suspension was added diethyl ether (5 mL) and themixture was chilled to 0° C. Neutralization with aq. NaOH and filtrationafforded 4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]-1-aminonaphthalene(XCIII) as a light brown solid (100 mg).

A mixture of 2-t-butyl-6-chloro-5-methylpyridine-4-carboxylic acidmethyl ester (2.27 g, 9.39 mmol) and LiOH monohydrate (2.36 g, 56.3mmol) in MeOH (30 mL) and water (10 mL) was stirred at room temperaturefor 24 h. The reaction was then concentrated and purified bychromatography on silica gel (eluent: 5% TFA in dichloromethane) to givethe corresponding carboxylic acid (1.41 g, 66.3%).

To a stirred solution of the above carboxylic acid (0.54 g, 2.36 mmol)and triethylamine (0.66 mL, 4.75 mmol) in THF (6 mtL) at −10° C. wasadded dropwise ethyl chloroformate (0.34 mL, 3.51 mmol). The resultingmixture was stirred at 0° C. for 1 h. A solution of sodium azide (0.40g, 6.0 mmol) in water (2 mL) was added and stirring was continued foranother 1 h. The mixture was extracted with toluene. The organic phasewas separated, dried with sodium sulfate, and concentrated to 15 mL. Itwas then heated at reflux for 2 h forming the isocyanate in situ, beforea solution of XCIII (0.39 g, 1.23 mmol) in dichloromethane (5 mL) wasadded. The reaction was stirred at room temperature overnight.Concentration and chromatography on silica gel (eluent: EtOAc) affordedthe title compound 17 (0.60 g, 89.9%).

Example 181-(5-tert-Butyl-2-methylphenyl)-3-(4-{6-[(3-methoxypropyl)methylamino]pyridin-3-yl}naphthalen-1-yl)urea

2,5-Dibromopyridine (100 mg) was heated to 115° C. in a seated tube inthe presence of 3-methoxypropyl-1-methylamine (2 mL) for 48 h to giveXCIV. A Suzuki coupling of XCIV with XCI and removal of the tert-butylcarbamate (analogous to the procedures in Example 17) afforded thedesired naphthylamine XCV.

5-tert-Butyl-2-methylaniline (0.56 mmol) was dissolved indichloromethane (20 mL). An equal volume of sat. aqueous sodiumbicarbonate was added, and the biphasic solution was cooled to 0° C.During the addition of phosgene (1.93 M in toluene, 0.80 mL), stirringwas stopped. Immediately afterward, stirring was resumed for 15 min withthe reaction mixture at 0° C. The layers were separated, the organicswere dried over solid magnesium sulfate, and concentrated toapproximately 5 mL of solution. The desired naphthylamine (XCVI, 0.47mmol) in 5 mL dichloromethane was added. The reaction mixture wasstirred at room temperature for 16 h. Flash chromatography using 7%MeOH/EtOAc as eluent followed with trituration with ether provided thetitle compound 18.

Example 191-[4-(6-Morpholin-4-ylmethylpyridin-3-yl)naphthalen-1-yl]-3-(3-trifluoromethyl-phenyl)urea

A stirred solution of 3-trifluoromethylaniline (4.7 mmol) in dry TUF (30mL) at 0° C. was treated with phenyl chloroformate (4.8 mmol). After 2h, the reaction mixture was quenched with aqueous, saturated sodiumbicarbonate solution and extracted with EtOAc. The combined organiclayers were washed with aqueous, saturated sodium bicarbonate solutionand brine, and were dried over solid MgSO₄. Concentration afforded thecarbamate XCVI (97%). A mixture of XCIII (Example 17) (0.06 mmol) andthe above-mentioned carbamate (0.05 mmol) was heated in a sealed tubefor 2 days. The reaction mixture was cooled to room temperature.PS-trisamine (100 mg, Argonaut) and PS-isocynate resins (150 mg,Argonaut) were added, and the reaction mixture was shaken for 3 days.The reaction mixture was filtered and concentrated to provide the titlecompound 19. Examples 20-25 exemplify the synthesis of aryl andheteroaryl amines which may be used as intermediate IV in Methods A-C(General Synthetic Methods) to prepare compounds of formula II or III.

Example 20 1-[5-tert-Butyl-2-(1H-pyrazol-4-yl)-phenyl]amine

Methyl 4-t-butylphenylacetate (20 mmol) was dissolved in MeOH (160 mL)and treated with water (40 mL) and LiOH monohydrate (30 mmol). Thereaction was allowed to stir at room temperature overnight. Volatileswere removed under reduced pressure; the remaining residue was dilutedwith water and neutralized to pH 4 with 1 N sulfuric acid. The resultingsolids were filtered, washed with water and dried to leave4-t-butylphenylacetic acid as an off-white solid (3.8 g, 99%). AnhydrousDMF (139 mmol) was cooled to 0° C. and treated with POCl₃ (79.6 mmol).After 5 min, 4-t-butylphenylacetic acid (19.9 mmol) was added and thereaction vessel was transferred to a 110° C. oil bath. The reactionmixture was stirred for 2 h, during which all solids dissolved. Aftercooling to room temperature, the reaction mixture was poured into astirred solution of NaPF₆ (19.8 mmol) in water (200 mL). Whenprecipitation of solids was complete, they were filtered, washed withwater, and dried to give XCVII (7.8 g, 97%).

XCVII (5 mmol) was taken up in EtOH (50 mL), and the resultingsuspension was treated with hydrazine hydrate (5 mmol). The reactionvessel was transferred to a 90° C. oil bath, and the reaction mixturewas stirred at reflux for 2 h. Volatiles were removed under reducedpressure after allowing the reaction mixture to cool to roomtemperature. The residue was taken up in ice water, solids werefiltered, washed with water and dried, giving4-(4-t-butylphenyl)pyrazole (973 mg, 97%).

4-(4-t-butylphenyl)pyrazole (0.5 mmol) was suspended in MeCN (2 mL),cooled to 0° C., and treated with NO₂BF₄ (0.6 mmol). The reactionmixture was allowed to warm slowly to room temperature and was stirredat RT for 2 h. Volatiles were removed under reduced pressure after thereaction was quenched with aqueous NaHCO₃. The residue was taken up inwater and extracted with CH₂Cl₂. The organics were combined, dried overMgSO₄, and concentrated to leave a yellow oil which was chromatographedon silica gel (eluent: CH₂Cl₂/EtOAc, 6:4) to give4-(4-t-butyl-2-nitrophenyl)pyrazole as a yellow crystalline solid (71mg, 58%).

4-(4-t-butyl-2-nitrophenyl)pyrazole (0.27 mmol) was dissolved in EtOH (3mL) and treated with 10% Pd/C (0.2 eq by weight of nitro compound),followed by NH₄CO₂H (2.7 mmol). After 30 min, the catalyst was filteredthrough a bed of diatomaceous earth, and the filtrate was concentratedunder reduced pressure. The residue was taken up in water, the resultingsolids were filtered, washed with water and dried (54 mg, 93%), givingthe title compound 20.

Example 21 3-Amino-2-methoxy-5-tert-butylpyridine

Ethyl nitroacetate (3.3 mL, 4.0 g, 29.7 mmol) was added to ammoniumhydroxide (25 mL, 11%) and stirred overnight as described by A. V. Ametet al., Russian Chemical Bulletin, 1996, 45(2), 393-398. The reactionwas basified with 4 N hydrochloric acid, extracted into ether (3×25 mL),then into EtOAc (3×100 mL). The combined EtOAc extracts were dried(magnesium sulfate), filtered and evaporated to dryness to affordnitroacetamide as a pale yellow solid (1.7 g, 16.3 mmol, 55%).

Trichloroaluminum (45.5 g, 341 mmol) was added slowly to 100 mL of icecold nitromethane under nitrogen. This was followed by a solution ofmalononitrile (21.5 mL, 22.6 g, 341 mmol) in 50 mL of nitromethane addeddropwise over one hour, keeping the temperature below 10° C. Next, asolution of tert-butyl chloride (88 mL, 74.9 g, 809 mmol) in 25 mL ofnitromethane was added slowly over 2.5 h, keeping the temperature under10° C. The reaction was capped and stored in the freezer for 60 h. Thereaction was quenched by adding saturated aqueous sodium bicarbonate(500 mL) dropwise over 4 h, keeping the temperature below 10° C. Theheterogeneous mixture was neutralized further with solid sodiumbicarbonate (50 g). The layers were separated and the aqueous layerextracted with methylene chloride (3×250 mL). The combined organicextracts were dried (magnesium sulfate) and concentrated in vacuo toafford 42 g of a partially crystalline brown oil. The residue was vacuumdistilled at 100° C. The first fraction was collected and then a solidbegan to form in the condenser. The cooling water was turned off and thecondenser heated with a heat gun to melt the solid. This fraction wascollected until no more solid formed in the condenser when cool waterwas run through it to afford the desired dinitrile as a low meltingcream solid (19 g, 155 mmol, 46%).

A solution of the above dinitrile (961 mg, 7.9 mmol) in anhydroushexanes (50 mL) was cooled to −70° C. in a dry ice/acetone bath undernitrogen. DIBAL-H (17.5 mL, 1.0 M in cyclohexane) was added dropwiseover 20 min. The mixture was stirred at −70° C. for 45 min, then at roomtemperature for 5 h. The reaction was cooled to 0° C., 2 M aqueoushydrochloric acid (45 mL) was added slowly, keeping the temperaturebelow 10° C. The mixture was stirred at room temperature for 15 h. Thelayers were separated and the aqueous layer extracted with ether (3×25mL). The combined organic extracts were dried (magnesium sulfate),filtered and evaporated to dryness to afford the desired dialdehyde as aviscous yellow oil (600 mg, 4.68 mmol, 60%).

A solution of the above aldehyde (271 mg, 2.11 mmol), nitroacetamide(223 mg, 2.14 mmol), and piperidine (20% in EtOH) (250 uL, 0.51 mmol) inabsolute EtOH (3 mL) was heated at 65° C. for 3 h. After cooling to roomtemperature, the reaction mixture was concentrated in vacuo. The residuewas purified by flash chromatography on silica gel (EtOAc) to give thedesired nitropyridone as a yellow solid (280 mg, 1.43 mmol, 67%).

A mixture of the nitropyridone (150 mg, 0.76 mmol), phosphorouspentachloride (199 mg, 0.96 mmol) and phosphorous oxychloride (1 drop)was heated to reflux in a sealed tube. After 2 h, the phosphorousoxychloride was removed in vacuo and the residue stirred in ice water(10 mL) for 18 h. The desired product was collected as a brown solid (95mg, 0.44 mmol, 58%).

To a solution of 2-chloro-3-nitro-5-tert-butyl pyridine (30 mg, 0.14mmol) in anhydrous MeOH (1.5 mL) under nitrogen was added a solution ofsodium methoxide (1.57 g sodium in 40 mL anhydrous MeOH) (85 uL, 0.14mmol). The reaction was heated in a sealed tube in an oil bath set at80-90° C. overnight. The volatiles were removed in vacuo, the residuetaken up in EtOAc (15 mL), washed with water (10 mL), brine (10 mL),dried (magnesium sulfate), filtered and evaporated to dryness. Flashchromatography of the residue on silica gel (10% EtOAc in hexanes) gavethe desired 2-methoxy-3-nitro-5-tert-butyl pyridine as a glassy yellowsolid (12 mg, 0.057 mmol, 41%).

To a suspension of the above intermediate (12 mg, 0.057 mmol) and Pd/C(10%, 14 mg) in absolute EtOH (1 mL) was added ammonium formate (22 mg,0.35 mmol) and the mixture was heated to 50° C. for 1 hour. The cooledreaction mixture was filtered through diatomaceous earth and rinsed withMeOH. The filtrate was evaporated to dryness to afford the titlecompound 21 as a brown solid (10 mg, 0.055 mmol, 100%).

Example 22 N-Acetyl-5-amino-3,3-dimethylindoline

A solution of oxindole (5.0 g, 37.5 mmol) in acetic anhydride (7.1 mL,75.1 mmol) and acetic acid (25 mL) was refluxed for 20 h. After coolingto room temperature, the reaction mixture was diluted with water (200mL). The resulting solids were filtered, washed with water and dried togive N-acetyl oxindole as a white solid (5.2 g, 79%).

A mixture of N-acetyl oxindole (2.0 g, 11.4 mmol), iodomethane (1.56 mL,25.1 mmol) and potassium carbonate (3.1 g, 22.8 mmol) in DMSO (20 mL)was stirred at room temperature for 20 h. The reaction mixture wasdiluted with water. The resulting solids were filtered, washed withwater and dried to give N-acetyl dimethyl oxindole as an orange solid(1.9 g, 84%).

A solution of N-acetyl dimethyl oxindole (500 mg, 2.5 mmol) in 3 Nsulfuric acid solution (7 mL) and THF (7 mL) was refluxed for 4 h. Aftercooling to room temperature, the reaction mixture was diluted withether. The ethereal layer was washed with water and brine, dried(magnesium sulfate), filtered and concentrated in vacuo. The residue waspurified by flash chromatography on silica gel (eluent: 30% EtOAc inhexanes) to give dimethyl oxindole as a red solid (228 mg, 57%).

A solution of dimethyl oxindole (220 mg, 1.4 mmol) in toluene (5 mL) wastreated with 65% Red-Al solution in toluene (0.64 mL, 2.05 mmol) at 80°C. After stirring at 100° C. for 4 h, the reaction mixture was quenchedwith IN sodium hydroxide solution. The organic layer was separated,washed with water and brine, dried (sodium sulfate), filtered andconcentrated in vacuo. The residue was purified by flash chromatographyon silica gel (eluent: 25% EtOAc in hexanes) to give dimethyl indolineas a light blue oil (121 mg, 60%).

A solution of dimethyl indoline (65 mg, 0.44 mmol) and triethylamine(0.12 mL, 0.88 mmol) in dry dichloromethane (3 mL) was treated withacetyl chloride (0.05 mL, 0.66 mmol) at 0° C. The mixture was allowed towarm to room temperature and was stirred for 16 h. Then the reactionmixture was quenched with water and the product was extracted intoether. The organic layer was washed with water and brine, dried (sodiumsulfate) filtered and concentrated in vacuo. The residue was purified byflash chromatography on silica gel (eluent: 30% EtOAc in hexanes) togive N-acetyl dimethyl indoline as a light yellow oil (68 mg, 82%).

A solution of N-acetyl dimethyl indoline (65 mg, 0.34 mmol) in aceticacid (2 mL) was treated with fuming nitric acid (24 L, 0.57 mmol) atroom temperature and the resulting mixture was stirred for 1 h. Thereaction mixture was quenched with sat. sodium bicarbonate solution andthe product was extracted into EtOAc. The organic layer was washed withwater and brine, dried (sodium sulfate), filtered and concentrated invacuo. The residue was purified by flash chromatography in silica gel(eluent: 50% EtOAc in hexanes) to give the desired nitrated indoline asa light orange solid (66 mg, 67%).

A mixture of N-acetyl-3,3-dimethyl-5-nitroindoline (64 mg, 0.27 mmol),ammonium formate (86 mg, 1.36 mmol) and 10% palladium on carbon (5 mg)in MeOH (5 mL) was stirred at room temperature for 2 h. The reactionmixture was filtered through a short plug of diatomaceous earth. Thefiltrate was concentrated in vacuo. The residue was purified by flashchromatography on silica gel (eluent: 50% EtOAc in hexanes) to give thetitle compound 22 as a white solid (48 mg, 87%).

Example 23 8-Amino-6-tert-butyl-3-oxo-4-N-methylbenzoxazine

To a solution of 4-tert-butyl-2,6-dinitrophenol (3.15 g, 13.13 mmol)dissolved in 100 mL acetonitrile was added ammonium formate (5.0 g, 78.8mmol) and 10% palladium on carbon (1.0 g). The mixture was refluxed for20 min, then allowed to cool and filtered through diatomaceous earth.The residues were washed with EtOAc and the combined organics wereevaporated in vacuo. The residue was taken up in dichloromethane andfiltered through a short plug of silica gel. After removal of solvent invacuo 2-amino-4-tert-butyl-6-nitro-phenol was obtained as a rust-redsolid (4.86 mmol; 37% yield).

To a solution of 2-amino-4-tert-butyl-6-nitrophenol (258 mg, 1.23 mmol)and benzyltriethylammonium chloride (280 mg, 1.23 mmol) in 5 mLchloroform was added finely powdered NaHCO₃ (413 mg, 4.92 mmol). Themixture was cooled to 0° C. and chloroacetyl chloride (0.12 mL, 1.47mmol) in 1.5 mL chloroform was added dropwise via syringe over 15 min.Once the addition was complete, the mixture was allowed to stir at 0° C.for 1 h. It was then allowed to warm to ambient temperature and finallywas gently refluxed for 6 h. The resulting crude orange mixture wasallowed to cool, then was filtered through diatomaceous earth to removea white precipitate, which was washed generously with more chloroform.After removal of the solvent in vacuo, the oily residue was treated withwater (40 mL) and agitated with a spatula, whereupon a yellowprecipitate formed. This pure 6-tert-butyl-8-nitro-3-oxo-benzoxazine wasfiltered, dried first under a stream of air, then in vacuo (1.05 mmol;85%).

To a solution of 6-tert-butyl-8-nitro-3-oxo-benzoxazine (51 mg, 0.20mmol) in 3.5 mL DMF at 0° C. was added sodium hydride (10 mg, 60% inmineral oil; 0.24 mmol) in one portion. After 20 min, methyl iodide (20uL, 0.24 mmol) was added via syringe. The mixture was allowed to warmslowly to ambient temperature overnight. The crude mixture was quenchedwith saturated aqueous ammonium chloride solution and extracted withEtOAc (3×10 mL). The combined organics were washed with water, thenbrine, then dried over sodium sulfate. Filtration and removal of thesolvents in vacuo afforded6-tert-butyl-8-nitro-3-oxo-4-N-methylbenzoxazine (100%).

6-tert-Butyl-8-nitro-3-oxo-4-N-methyl-benzoxazine (53 mg, 0.2 mmol) wasdissolved in 12.5 mL acetonitrile. Cyclohexene (0.20 mL, 2.0 mmol) and10% palladium-on-carbon (75 mg) were added. The mixture was refluxed for1 h, then cooled to ambient temperature and filtered throughdiatomaceous earth. The residues were washed with EtOAc and the combinedorganics were evaporated in vacuo to afford the title compound 23(100%).

Example 24 7-Amino-5-tert-butyl-3H-benzoxazol-2-one

To a solution of 2-amino-4-tert-butyl-6-nitrophenol (300 mg, 1.43 mmol)and pyridine (0.30 mL) in methylene chloride (30 mL) was added4-nitrophenylchloroformate (280 mg, 1.39 mmol). The mixture was stirredfor 24 h. The resulting solution was washed with aqueous sodiumbicarbonate (2×20 mL), dried over solid magnesium sulfate andconcentrated to an orange solid. Column chromatography (silica gel,eluant=40% EtOAc/petroleum ether) afforded5-tert-butyl-7-nitro-3H-benzoxazol-2-one (70%).

5-tert-Butyl-7-nitro-3H-benzoxazol-2-one (200 mg, 0.9 mmol) wasdissolved in EtOH (10 mL). Cyclohexene (4 mL) and 10% palladium oncarbon (50 mg) were added. The mixture was refluxed for 3 h, then cooledto ambient temperature and filtered through diatomaceous earth. Columnchromatography (silica gel, eluant=25% EtOAc/petroleum ether) affordedthe title compound 24 (70%).

Example 25 7-Amino-5-tert-butyl-2-methylbenzoxazole

2-Amino-4-tert-butyl-6-nitrophenol was dissolved in triethylorthoacetate (10 mL). The reaction mixture was stirred overnight at 100°C. Evaporation of volatiles in vacuo afforded5-tert-butyl-2-methyl-7-nitrobenzoxazole (110 mg).

5-tert-Butyl-2-methyl-7-nitrobenzoxazole (100 mg, 0.4 mmol) wasdissolved in EtOH (20 mL). The catalyst (10% Pd/C, 100 mg) was addedfollowed by ammonium formate (160 mg, 0.3 mmol). The resultingheterogenous mixture was stirred at 100° C. for 1 h. Filtration followedby evaporation provided the title compound 25 (85 mg).

Examples 26-29 exemplify the synthesis of four heteroaryl amines whichmay be used as intermediate IV in Methods A-C (General SyntheticMethods) to prepare compounds of formula I or Ia.

Example 26 5-(5-Amino-3-tert-butylpyrazol-1yl)-2-methylbenzamide

3-Iodo-4-methylphenyl amine (10 g, 43 mmol) was dissolved in 6 N HCl (40mL), cooled to 0° C., and vigorously stirred throughout the procedure.Sodium nitrite (2.9 g, 1.03 equiv.) was dissolved in water (5 mL) andthis solution was added to the reaction in a dropwise fashion. After 30min, tin (II) chloride dihydrate (22.8 g, 1 mol) in 6 N HCl (100 mL) wasadded via addition funnel, and the reaction slurry was stirred at 0° C.for 3 h. The pH was adjusted to 14 with 40% aqueous sodium hydroxidesolution and the aqueous mixture was extracted with EtOAc, (6×50 mL),dried (MgSO₄), and concentrated to give 3-iodo-4-methylphenylhydrazine(7 g, 57%). This material was used directly without furtherpurification.

A solution of the above phenylhydrazine (5.08 g, 22 mmol) and4,4-dimethyl-3-oxopentanenitrile (3.06 g, 1.1 equiv.) in EtOH (100 mL)containing conc. HCl (3 mL) was refluxed for 17 h, then cooled to roomtemperature. The pH was adjusted to 14 with 40% aqueous sodium hydroxidesolution. The aqueous mixture was extracted with EtOAc, (3×50 mL), dried(MgSO₄), and concentrated to give5-tert-butyl-2-(3-iodo-4-methyl-phenyl)-2H-pyrazol-3-ylamine (6.3 g,86%). This material was used directly without further purification.

5-tert-Butyl-2-(3-iodo-4-methyl-phenyl)-2H-pyrazol-3-ylamine (2 g, 5.6mmol) was combined with zinc cyanide (397 mg, 0.6 eq.) andtetrakis(triphenylphosphine)-palladium(0) (325 mg, 5 mol %) indeoxygenated dimethylformamide (10 mL). The resulting yellow slurry washeated at 100° C. for 4 h, cooled to room temperature, diluted withbrine and 2 N HCl. The aqueous mixture was extracted with EtOAc (6×10mL), dried (MgSO₄), and concentrated. The residue was purified by flashchromatography eluting with 20% EtOAc/petroleum ether to give 1.3 g(91%) of the desired nitrile.

The above nitrile (150 mg, 0.6 mmol) in EtOH (5 mL) was heated to 100°C. in the presence of 10 N NaOH for 2 h. The reaction was cooled to roomtemperature, neutralized with 50% HCl, extracted with EtOAc (6×10 mL),dried (MgSO₄) and concentrated to give the title compound 26 (130 mg,80%).

Example 27

5-Amino-2-methoxypyridine (5.0 g, 40 mmol) was dissolved in 6 N HCl (10mL), cooled to 0° C., and vigorously stirred throughout the procedure.Sodium nitrite (2.8 g, 41 mmol) was dissolved in water (10 mL) and thissolution was added to the reaction solution. After 30 min, tin (II)chloride dihydrate (52 g, 230 mmol) in 6 N HCl (20 mL) was added, andthe reaction slurry was stirred at 0° C. for 2.5 h. The pH was adjustedto 13 with 40% aqueous potassium hydroxide solution. Ethyl ether wasadded and the mixture was extracted with EtOAc (4×70 mL), dried (MgSO₄)and concentrated to give 5-hydrazino-2-methoxypyridine as an orangesolid (5.1 g).

A solution of 5-hydrazino-2-methoxypyridine (2.5 g, 18 mmol) and 4,4-dimethyl-3-oxopentanenitrile (2.3 g, 18 mmol) in toluene (50 mL) wasrefluxed for 17 h in a flask fitted with a Dean-Stark trap, then cooledto room temperature. The reaction mixture was concentrated and theresidue purified by column chromatography on silica gel, eluting with30% EtOAc/petroleum ether to give the title compound 27 as a tan solid(3.5 g, 80%).

Example 28 5-Amino-3-tert-butyl-1-(2-pyridone-5-yl)pyrazole

To a solution of the product of Example 27 (0.6 g, 2.4 mmol) in aceticacid (3 mL) was added 48% HBr in acetic acid (3 mL). The reactionmixture was heated to 120° C. for 15 min, cooled to room temperature,and the pH was adjusted to 7.5 with 10% aqueous sodium hydroxidesolution. The aqueous mixture was extracted with EtOAc (4×15 mL), dried(MgSO₄), and concentrated to give a tan solid. The title compound 28(0.46 g, 82%) was obtained after recrystallization from ether.

Example 29 5-Amino-3-tert-butyl-1-(2-cyanoethyl)pyrazole

A solution of 2-cyanoethylhydrazine (3.0 g, 35 mmol) and4,4-dimethyl-3-oxopentanenitrile (4.2 g, 34 mmol) in toluene (50 mL) wasrefluxed for 17 h in a flask fitted with a Dean-Stark trap, then cooledto room temperature. The slurry was filtered and the filtrate wasconcentrated. Column chromatography of the residue on silica gel,eluting with 50% EtOAc/petroleum ether) afforded the title compound 29as a colorless solid (2.6 g, 40%).

Example 301-[5-tert-Butyl-2-(2-methylthiopyrimidin-5-yl)-2H-pyrazol-3-yl]-3-{4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl}urea

Pinacolone (100 mmol) and diethyloxalate (120 mmol) were dissolved inTHF (200 mL), cooled to −78° C. and treated with LiHMDS (120 mmol, 1 Min THF). The ice bath was removed and the reaction allowed to warm toroom temperature. After 2 h, volatiles were removed and the cruderesidue was dissolved in glacial HOAc (200 mL). Hydrazine monohydrate(110 mmol) was added and the reaction placed in a 90° C. oil bath andstirred overnight. The HOAc was removed under reduced pressure and thecrude residue was taken up in aqueous NaHCO₃ to give a pH 6 solution.Solids were filtered, washed with water and dried to give the desiredpyrazole ester (12.9 g, 66%).

KOt-Bu (67 mmol) was dissolved in DMSO (120 mL). The pyrazole ester fromabove (12 g, 61 mmol) was added in one portion and the reaction wasstirred for 15 min. t-Butyl bromoacetate (92 mmol) was added and thereaction was stirred at room temperature for 45 min. DMSO was removedunder reduced pressure and the crude residue was diluted with ice waterand extracted with CH₂Cl₂. The organics were combined, dried over MgSO₄and concentrated to leave an isomeric mixture of pyrazoles as an orangeoil (21 g). The desired isomer was isolated as an oil via silica gelchromatography, eluting with CH₂Cl₂ (13.3 g, 70%).

The pyrazole diester (13.3 g, 43 mmol) was dissolved in neat TFA (150mL) and stirred at room temperature for 3 h. Volatiles were removed andthe crude residue was diluted with ice water and extracted with CH₂Cl₂.Organics were combined, washed with water, dried over MgSO₄ andconcentrated to leave the desired carboxylic acid as a thick oil thatpartially crystallized (10.2 g, 94%).

Anhydrous DMF (282 mmol) was cooled to 0° C. and treated with POC1₃ (161mmol). After 5 min, the above pyrazole acetic acid derivative (10.2 g,40 mmol) was added and the suspension was transferred to a 110° C. oilbath. The reaction was stirred for 2 h, during which all solidsdissolved. After cooling to room temperature, the reaction was pouredinto a stirred solution of NaPF₆, (80 mmol) in water (400 mL). Whenprecipitation of solids was complete, they were filtered, washed withwater and dried giving the desired vinamidinium salt XCVIII (14.6 g,78%). Salt XCVIII from above (233 mg, 0.5 mmol) was taken up in DMSO (10mL) and treated with S-methylisothiourea sulfate (0.25 mmol) and K₂CO₃(0.25 mmol). The reaction was transferred to a 90° C. oil bath andstirred for 2 h. Volatiles were removed under reduced pressure afterallowing the reaction to cool to room temperature. The residue was takenup in ice water and extracted with diethyl ether. Organics werecombined, dried over MgSO₄ and concentrated to leave a brown tar. Thedesired ethyl ester was purified by chromatography on a silica gelcolumn eluting with CH₂Cl₂/EtOAc, 1:1 to give a yellow oil thatcrystallized upon standing (157 mg, 98%).

The ester from above (150 mg, 0.47 mmol) was dissolved in MeOH (4 mL)and water (1 mL), treated with LiOH monohydrate (0.7 mmol) and stirredat room temperature overnight. Volatiles were removed, the residue wasdiluted with water, neutralized to pH 4 with 1N sulfuric acid. Solidswere filtered, washed with water and dried (113 mg, 82%).

The resulting carboxylic acid (105 mg, 0.36 mmol) was suspended inbenzene (4 mL) and treated with triethylamine (0.61 mmol). The resultingsolution was treated with diphenylphosphoryl azide (DPPA) (0.54 mmol)and allowed to stir at room temperature for 6 h. Organics were washedwith aqueous NaHCO₃, water, dried over MgSO₄ and filtered. The resultingsolution was treated with LXXXIV (Example 4) (115 mg, 0.36 mmol) and thereaction was placed in a 90° C. oil bath for 1 h. Volatiles were removedand the crude residue was purified on two preparative TLC plates elutingwith CH₂Cl₂/MeOH, 9:1 to give the title compound 30 as an off-whitesolid (61 mg, 28%).

By substituting for the S-methylisothiourea sulfate used in reactionwith XCVIII, one may obtain other substituted pyrimidines correspondingto XCVIV. For example, using acetamidine hydrochloride would provide the2-methylpyrimidine analog of XCVIV. O-Methylisothiourea sulfate andguanidine carbonate would give the 2-methoxypyrimidine and2-aminopyrimidine analogs respectively. By replacing S-methylisothioureasulfate with hydrazine monohydrate or N-methylhydrazine, one may obtaina pyrazol-4-yl or 1-methylpyrazol-4-yl ring respectively in place of thesubstituted pyrimidine in XCVIV. Each of these analogs of XCVIV may betaken on as described above to provide the corresponding analogs of 30.

5 Examples 31-36 exemplify syntheses of substituted napthylamines whichmay be used as intermediate VI (D′-NH₂) as described in Methods B and Cin General Synthetic Methods to produce various compounds of theinvention

Example 31 5-(4-Aminonapthalen-1-yl)-2-pyridin-3-ylmethylphenol

To a tube containing a solution of 2.0 g of 1-amino-4-bromonaphthalene(9.0 mmol; 1 equiv.) in 70 mL DMF were added 1.75 mL of2-cyclohexen-1-one (18.0 mmol; 2.0 equiv.), 2.3 g of sodium bicarbonate(27.0 mmol; 3.0 equiv.) and 186 mg of 1,3-bis-(diphenylphosphino)propane(dppp; 0.45 mmol; 0.05 equiv.). A stream of dry nitrogen gas was bubbledthrough the mixture for 15 min, then 316 mg ofbis-(triphenylphosphino)palladium(II) chloride (0.45 mmol; 0.05 equiv.)was added and the tube was sealed. The mixture was heated at 150° C. for8 h, then cooled to ambient temperature, diluted with EtOAc (150 mL) andfiltered through diatomaceous earth. The mixture was washed with water,then brine. The organic layer was dried (MgSO₄), filtered andconcentrated. The crude oil was purified by column chromatography onSiO₂ using 10 to 50% EtOAc in hexane mixtures as eluents to give 2.0 gof a thick liquid consisting of3-(4-aminonapthalen-1-yl)cycloxex-2-enone and DMF (molar ratio 1:2respectively; 5.22 mmol of naphthylamine; 58% of theoretical yield).

To a solution of 4.0 g of 3-(4-aminonapthalen-1-yl)cycloxex-2-enone: DMF(1: 2; 10.4 mmol; 1 equiv.) in 50 mL toluene was added 2.72 g ofdi-tert-butyl dicarbonate (12.5 mmol; 1.2 equiv.) and 1.5 mLtriethylamine (10.4 mmol; 1 equiv.). The mixture was heated to 100° C.overnight, then cooled to ambient temperature. The reaction mixture waswashed with 0.1% aqueous HCl (2×50 mL), water, brine, dried (MgSO₄),filtered and concentrated. The crude product precipitated and was washedwith 10% EtOAc in hexane to afford, after filtration, 2.5 g of desiredtert-butyl carbamate (7.4 mmol; 71% of theoretical yield).

To a solution of 186 mg of the above tert-butyl naphthyl carbamate (0.55mmol; 1 equiv.) in 1.6 mL anhydrous tert-butanol was added 52 uL ofpyridine-3-carboxaldehyde (0.55 mmol; 1 equiv.) and 1.65 mL potassiumtert-butoxide solution (1.0 M; 1.32 mmol; 3 equiv.). The mixture washeated to reflux overnight, then cooled. MeOH (5 mL) and HCl solution indioxane (4.0 M) were added until pH˜1, the reaction was then stirred for1.5 h at ambient temperature. The mixture was then quenched withsaturated NaHCO₃ aqueous solution and extracted with EtOAc (2×50 mL).The aqueous layer was treated with 4 N NaOH aqueous solution until pH˜12and extracted 2 more times. The combined organic extracts were washedwith brine, dried (MgSO₄), filtered and concentrated to afford a mixtureof crude products, including naphthylamine still protected as thecarbamate. The residue was therefore taken up in dichloromethane (3 mL),treated with 2 mL TFA and left stirring over a weekend at ambienttemperature. The mixture was quenched and neutralized with saturatedaqueous NaHCO₃, extracted with dichloromethane (3×50 mL), dried (MgSO₄)and filtered. The volatiles were removed in vacuo and the crude productpurified by column chromatography on SiO₂ using 50 to 100% EtOAc inhexane eluent mixtures giving 35 mg (0.11 mmol; 20% of theoreticalyield) title compound 31.

Example 325-(4-Aminonapthalen-1-yl)-2-(tetrahydrofuran-3-ylmethyl)phenol

To a solution of 3.16 g of tetrahydro-3-furoic acid (27 mmol; 1 equiv.)in 25 mL anhydrous dichloromethane was added 7.85 g ofdicyclohexylcarbodiimide (38 mmol; 1.4 equiv.) and 4.54 mL triethylamine(32.6 mmol; 1.2 equiv.). N-methyl-20 methanolamine hydrochloride wasthen added, followed by 60 mg of DMAP (4-dimethylamino)pyridine. Anexothermic reaction ensued and a further 25 mL of dichloromethane wereadded. The mixture was stirred at ambient temperature overnight, thenfiltered through diatomaceous earth and concentrated. The residue wastreated with ether and the white solid filtered off and removed. Thesolvent was removed from the mother liquor and the residue purified bycolumn chromatography on SiO₂ using 15-25% EtOAc in hexanes as eluentmixtures to provide the desired amide as a colorless oil (55% oftheoretical yield) that still contained 10% of dicyclohexyl urea. Thiswas used without further purification in the next reaction.

To a solution of 1.0 g of the above amide (6.28 mmol; 1 equiv.) in 60 mLanhydrous THF at −78° C. was added 12.6 mL of 1.0 M DIBAL-H solution intoluene dropwise via syringe (12.6 mmol; 2.0 equiv.). After stirring 30min at −78° C. the reaction mixture was quenched with 50 mL MeOH and 50mL water. The reaction mixture was transferred to a separatory funneland 250 mL ether were added. 1 N HCl aqueous solution was added untilall the solids had dissolved. The layers were separated and the aqueousportion was extracted further with 2×100 mL ether. The combined organicswere washed with saturated aqueous NaHCO₃ solution, then brine, driedover Na₂SO₄, filtered and concentrated. The crude product was purifiedby chromatography on silica gel using 0-5% MeOH in dichloromethane aseluent mixtures. The desired 3-tetrahydrofuroic aldehyde was obtained asa very volatile, impure colorless oil (200 mg).

To a solution of 200 mg of tert-butyl naphthyl carbamate (0.59 mmol; 1equiv.) in 1.6 mL anhydrous tert-butanol was added 200 mg of3-tetrahydrofuroic aldehyde from above (excess) and 1.78 mL potassiumtert-butoxide solution in tert-butanol (1.0 M; 1.78 mmol; 3 equiv.). Themixture was heated to 40° C. overnight, then cooled and quenched withNH₄Cl saturated aqueous solution. The product was extracted with adichloromethane/methanol mixture (3×100 mL). The combined extracts werewashed with brine, dried over MgSO₄, and concentrated. ¹H NMR analysisrevealed that only 10% of the enone was consumed. The residue (300 mg)was dissolved in 4.0 mL dichloromethane and treated with 4 mL of a 1:1mixture dichloromethane: TFA. The mixture was stirred for 1.5 h, thenneutralized with saturated NaHCO₃ aqueous solution, basified with 4 NNaOH solution and extracted with dichloromethane/methanol (3×100 mL).The combined organic extracts were washed with brine, dried (MgSO₄) andfiltered and concentrated. The crude product was purified by columnchromatography on silica gel using 10 to 50% EtOAc in hexane eluentmixtures to give the title compound 32 (35 mg 0.11 mmol; 19% oftheoretical yield).

Example 33 4-[5-(4-Aminonapthalen-1-yl)pyridin-2-yloxy]butyronitrile

To 2,5-dibromopyridine (500 mg, 2.1 mmol) and 3-cyano-1-propanol (270mg, 3.1 mmol) in DMSO (2 mL) was added 1M sodium hexamethyldisilazide(2.1 mL, 2.1 mmol). The reaction was stirred at room temperatureovernight. EtOAc was added to the reaction and the mixture was washedwith water (2×10 mL). The EtOAc fraction was dried over anhydrous sodiumsulfate and evaporated on a rotary evaporator. The crude product waspurified by flash column chromatography over silica gel using40%EtOAc/hexanes to give 200 mg of 5-bromo-2-cyanopropyloxypyridine as apale yellow solid (39.3%).

To the above intermediate (100 mg, 0.4 mmol) and CBZ-protectednaphthylboronic acid XCVIX (prepared as described for the Boc-analog XCIin Example 17) (200 mg, 0.62 mmol) in DME (4 mL) was added 2M sodiumcarbonate solution (2 mL). The solution was purged with nitrogen for 10min and to this was added palladium tetrakistriphenylphosphine (20 mg).The reaction was heated at 90° C. for 48 h and then cooled to roomtemperature. EtOAc was added to the reaction and the mixture was washedwith water (2×10 mL). The EtOAc fraction was dried over anhydrous sodiumsulfate, filtered and concentrated. The crude product was purified byflash column chromatography over silica gel eluting with40%EtOAc/hexanes to give 70 mg of product (39%).

To the above coupled product (70 mg, 0.16 mmol) in EtOH (5 mL) was addedcyclohexene (263 mg, 3.2 mmol) and 10%Pd/C (20 mg). The reaction washeated under nitrogen overnight and cooled to room temperature. Thereaction was filtered over diatomaceous earth, washed with MeOH andconcentrated. The crude product was purified by flash columnchromatography over silica gel eluting with 50% EtOAc/hexanes to give 15mg of the title compound 33 (31%).

Example 34[5-(4-Aminonapthalen-1-yl)pyridin-2-yl]-(tetrahydrothiopyran-4-yl) aminedihydrochloride

To tetrahydro-1,4-thiopyrone (2.0 g, 17.2 mmol) and hydroxylaminehydrochloride (2.0 g, 28.7 mmol) in EtOH (10 mL) was added sodiumacetate trihydrate (4.0 g, 29.4 mmol) in 20 mL water. The reaction washeated at reflux for 3 h, cooled to room temperature and concentrated to15 mL on a rotary evaporator. The residue was cooled in an ice-bath andfiltered to give 2.0 g of the oxime product as a white solid m.p. 80-83°C. (88.7%).

To a dry flask containing THF (20 mL) and IM lithium aluminium hydridein diethyl ether (19 mL) at room temperature, was added the oxime fromabove (500 mg, 3.82 mmol). The reaction was heated at reflux for 3 h,cooled to room temperature and the excess LAH was quenched withice/water. Extraction with EtOAc and concentration gave 340 mg (76%) ofthe desired 4-aminotetrahydrothiopyran.

To the above amine (170 mg, 1.4 mmol) in dry pyridine (1 mL) was added2,5-dibromopyridine (250 mg, 1.1 mmol) and the reaction was heated at110-120° C. for 5 days. The reaction was extracted with EtOAc, washedwith water, dried over anhydrous sodium sulfate and concentrated to givethe crude product. The crude product was purified by flash columnchromatography over silica gel using 30% EtOAc/hexanes as eluent to give100 mg of pure product (33.3%).

To the above intermediate (80 mg, 0.293 mmol) and BOC-protectednaphthylboronic acid XCI (Example 17) (140 mg, 0.488 mmol) in DME (4 mL)was added 2 M sodium carbonate (2 mL) andbis(triphenylphosphine)palladium chloride (15 mg). The reaction washeated at 90° C. under nitrogen for 18 h and cooled to room temperature.The reaction was extracted with EtOAc, washed with water, dried overanhydrous sodium sulfate and concentrated to give the crude product. Thecrude product was purified by flash column chromatography over silicagel using 30% EtOAc/hexanes as eluent to give 110 mg of pure product XCX(86.0%)

To the XCX (35 mg, 0.08 mmol) in dioxane (1 mL) was added 4 MHCl/dioxane (0.6 mL). The reaction was stirred at room temperature for48 h. Addition of diethyl ether gave the product as the hydrochloridesalt which was filtered, giving 18 mg (55%) of the title compound 34.

Example 35[5-(4-Aminonapthalen-1-yl)pyridin-2-yl]-(tetrahydropyran-4-yl) aminedihydrochloride

To 2-amino-5-bromopyridine (250 mg, 1.44 mmol) and BOC-protectednaphthylboronic acid XCI (Example 17) (688 mg, 2.4 mmol) in 5 mL DME wasadded 2 M sodium carbonate (2.5 mL) and bis(triphenylphosphine)palladiumchloride (30 mg). The reaction was heated at 90° C. under nitrogen for18 h and cooled to room temperature. The reaction mixture was extractedwith EtOAc, washed with water, dried over anhydrous sodium sulfate andconcentrated. The residue was purified by flash column chromatographyover silica gel eluting with 40% EtOAc/hexanes to give 370 mg coupledproduct XCX (76.4%).

To the above intermediate (200 mg, 0.597 mmol) and tetrahydropyranone(120 mg, 1.19 mmol) in dichloroethane (5 mL) was added glacial aceticacid (0.2 mL, 3.58 mmol) and sodium triacetoxyborohydride (380 mg, 1.79mmol). The reaction was stirred at room temperature for 48 h and thenextracted with EtOAc, washed with water, dried over anhydrous sodiumsulfate and concentrated. The residue was purified by flash columnchromatography over silica gel using 50% EtOAc/hexanes as eluent to give120 mg XCXI (48.0%).

The above product, XCX, was dissolved in dichloromethane (3 mL) andtreated with trifluoroacetic acid (1 mL). The reaction was stirred for 3h and concentrated. The residue was dissolved in EtOAc (20 mL), washedwith sodium bicarbonate solution, dried over anhydrous sodium sulfateconcentrated to give 90 mg of the title compound 35 (98.5%).

Example 36[5-(4-Aminonapthalen-1-yl)pyridin-2-yl]-(1-methylpiperidin-4-yl) amine

To a mixture of XCX (Example 35) (110 mg, 0.33 mmol) and1-methyl-4-piperidone (80 mg, 0.7 mmol) in dichloroethane (6 mL) wasadded glacial acetic acid (120 mg, 2.0 mmol) and sodiumtriacetoxyborohydride (220 mg, 1.03 mmol). The reaction was stirred atroom temperature for 96 h and then extracted with EtOAc, washed withwater, dried over anhydrous sodium sulfate and concentrated. The residuewas purified by flash column chromatography over silica gel using 10%MeOH/CH₂Cl₂/0.1%TEA as eluent to give 60 mg of pure product (42.0%).

The above product was dissolved in dichloromethane (3 mL) and treatedwith trifluoroacetic acid (1 mL). The reaction was stirred for 2.5 h andthe concentrated to give 94 mg of the title compound 36 (100%).

Example 37

Example 37 illustrates the synthesis of a compound of formula III inwhich E is O.

[4-(6-Morpholin-4-ylmethylpyridin-3-yl)napthalen-1-yl]carbamic acid3-tert-butylphenyl ester

LXXXIV (Example 4) (100 mg, 0.31 mmol) was dissolved in dichloromethane(20 mL). An equal volume of sat. aqueous sodium bicarbonate was added,and the biphasic solution was cooled to 0° C. During the addition ofphosgene (1.93 M in toluene, 0.40 mL), stirring was stopped. Immediatelyafterward, stirring was resumed for 15 min with the reaction mixture at0° C. The layers were separated, the organics were dried over solidmagnesium sulfate, and concentrated to approximately 5 mL of solution.3-tert-Butylphenol (100 mg, 0.67 mmol) in dichloromethane (5 mL) wasadded. The reaction mixture was stirred at room temperature for 19 h.Flash chromatography using EtOAc as eluent provided 71 mg of the titlecompound 37.

Example 38

Example 38 illustrates the synthesis of a compound of formula III inwhich E is CH₂.

2-(5-tert-Butyl-2-methoxyphenyl)-N-[4-(6-morpholin-4-ylmethylpyridin-3-yl)napthalen-1-yl]acetamide

LXXXIV (Example 4) (100 mg, 0.4 mmol) and the sodium salt of5-tert-butyl-2-methoxyphenylacetic acid (154 mg, 0.4 mmol) weredissolved in dichloromethane (15 mL).1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (172 mg, 0.9mmol) was added, and the reaction mixture was stirred at ambienttemperature for 16 h. HPLC purification afforded 30 mg of the titlecompound 38.

The following additional examples were prepared by methods analogous tothose described above:

1-(2-tert-Butyl-5-methyl-pyridin-4-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;

1-(5-tert-Butyl-2-methylphenyl]-3-{4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl}urea:

1-(3,3-Dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea

1-(3-Amino-5-tert-butyl-2-methoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea

1-(3-tert-Butyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;

1-(4-Methyl-biphenyl-3-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;

1-(4-tert-Butyl-biphenyl-2-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;

1-(5-{4-[3-(5-tert-Butyl-2-methoxy-phenyl)-ureido]-naphthalen-1-yl}-pyridin-2-ylmethyl)-piperidine-3-carboxylicacid amide

1-(5-Isopropyl-2-methyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;

1-(5-sec-Butyl-2-methoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;

1-(5-tert-Butyl-2-methoxymethyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;

1-(5-tert-Butyl-2-methoxy-phenyl)-3-(4-{6-[(tetrahydro-furan-3-ylamino)-methyl]-pyridin-3-yl}-naphthalen-1-yl)-urea

1-(5-tert-Butyl-2-methoxy-phenyl)-3-(4-{6-[4-(3-methoxy-phenyl)-piperazin-1-ylmethyl]-pyridin-3-yl}-naphthalen-1-yl)-urea

1-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(5-morpholin-4-ylmethyl-pyrazin-2-yl)-naphthalen-1-yl]-urea

1-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(6-{[(2-cyano-ethyl)-(tetrahydro-furan-2-ylmethyl)-amino]-methyl}-pyridin-3-yl)-naphthalen-1-yl]-urea

1-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(6-{[(2-cyano-ethyl)-pyridin-3-ylmethyl-amino]-methyl}-pyridin-3-yl)-naphthalen-1-yl]-urea

1-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;

1-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(6-thiomorpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea

1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(1-oxo-14-thiomorpholin-4-ylmethyl)-pyridin-3-yl]-naphthalen-1-yl}-urea

1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(1-oxo-tetrahydro-thiopyran-4-ylamino)-pyridin-3-yl]-naphthalen-1-yl}-urea

1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(2,6-dimethyl-morpholin-4-ylmethyl)-pyridin-3-yl]-naphthalen-1-yl}-urea

1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(2,6-dimethyl-piperidin-1-ylmethyl)-pyridin-3-yl]-naphthalen-1-yl}-urea

1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(2-methoxymethyl-morpholin-4-ylmethyl)-pyridin-3-yl]-naphthalen-1-yl}-urea

1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(2-methyl-3-oxo-piperazin-1-ylmethyl)-pyridin-3-yl]-naphthalen-1-yl}-urea

1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(2-oxa-5-aza-bicyclo[2.2.1]hept-5-ylmethyl-pyridin-3-yl]-naphthalen-1-yl}-urea

1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(2-thia-5-aza-bicyclo[2.2.]hept-5-ylmethyl-pyridin-3-yl]-naphthalen-1-yl}-urea

1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(3-oxo-piperazin-1-ylmethyl)-pyridin-3-yl]-naphthalen-1-yl}-urea

1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(4-methyl-piperazin-1-ylmethyl)-pyridin-3-yl]-naphthalen-1-yl}-urea

1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(4-pyridin-2-yl-piperazin-1-ylmethyl)-pyridin-3-yl]-naphthalen-1-yl}-urea

1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(morpholine-4-carbonyl)-pyridin-3-yl]-naphthalen-1-yl}-urea

1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(pyridin-3-yloxy)-pyridin-3-yl]-naphthalen-1-yl}-urea

1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(tetrahydro-pyran-4-ylamino)-pyridin-3-yl]-naphthalen-1-yl}-urea

1-(5-tert-Butyl-2-methyl-phenyl)-3-(4-{6-[(3-methoxy-propyl)-methyl-amino]-pyridin-3-yl}-naphthalen-1-yl)-urea;

1-(5-tert-Butyl-2-methyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;

1-(5-tert-Butyl-2-methyl-pyridin-3-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;

1-(6-tert-Butyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea

1-[4-(6-{[B is-(2-cyano-ethyl)-amino]-methyl}-pyridin-3-yl)-naphthalen-1-yl]-3-(5-tert-butyl-2-methoxy-phenyl)-urea

1-[5-(1,1-Dimethyl-propyl)-2-methoxy-phenyl]-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;

1-[5-tert-Butyl-2-(1H-pyrazol-4-yl)-phenyl]-3-[4-(6-morpholin-4-ylmethyl-pyridin-naphthalen-1-yl]-urea;

1-[5-tert-Butyl-2-(2-methyl-pyrimidin-5-yl)-phenyl]-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;

1-[5-tert-Butyl-2-(3-hydroxy-propyl)-phenyl]-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;

1-[5-tert-Butyl-2-(morpholine-4-carbonyl)-phenyl]-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;

N-(5-{4-[3-(5-tert-Butyl-2-methoxy-phenyl)-ureido]-naphthalen-1-yl}-pyridin-2-yl)-acetamide

N-(5-tert-Butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-ureido}-phenyl)-acetamide

N-(5-tert-Butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1yl]-ureido}-phenyl)-N-methyl-acetamide

N-(5-tert-Butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-ureido}-phenyl)-2,2,2-trifluoro-acetamide

N-(5-tert-Butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-ureido}-phenyl)-methanesulfonamide.

ASSESSMENT OF BIOLOGICAL PROPERTIES Inhibition of TNF Production in THPCells

The inhibition of cytokine production can be observed by measuringinhibition of TNFα in lipopolysaccharide stimulated THP cells (forexample, see W. Prichett et al., 1995, J. Inflammation, 45, 97). Allcells and reagents were diluted in RPMI 1640 with phenol red andL-glutamine, supplemented with additional L-glutamine (total: 4 nM),penicillin and streptomycin (50 units/ml each) and fetal bovine serum(FBS, 3%) (GIBCO, all conc. final). Assay was performed under sterileconditions; only test compound preparation was nonsterile. Initial stocksolutions were made in DMSO followed by dilution into RPMI 1640 2-foldhigher than the desired final assay concentration. Confluent THP. 1cells (2×10⁶ cells/ml, final conc.; American Type Culture Company,Rockville, Md.) were added to 96 well polypropylene round bottomedculture plates (Costar 3790; sterile) containing 125 μl test compound (2fold concentrated) or DMSO vehicle (controls, blanks). DMSOconcentration did not exceed 0.2% final. Cell mixture was allowed topreincubate for 30 min, 37° C., 5% CO₂ prior to stimulation withlipopolysaccharide (LPS; 1 μg/ml final; Siga L-2630, from E. coliserotype 011.B4; stored as 1 mg/ml stock in endotoxin screened distilledH₂O at −80° C). Blanks (unstimulated) received H₂O vehicle; finalincubation volume was 250 pl. Overnight incubation (18-24 hr) proceededas described above. Assay was terminated by centrifuging plates 5 min,room temperature, 1600 rpm (400×g); supernatants were transferred toclean 96 well plates and stored −80° C. until analyzed for human TNFA bya commercially available ELISA kit (Biosource #KHC3015, Camarillo,Calif.). Data was analyzed by non-linear regression (Hill equation) togenerate a dose response curve using SAS Software System (SAS institute,Inc., Cary, N.C.). The calculated IC50 value is the concentration of thetest compound that caused a 50% decrease in the maximal TNFa production.

Preferred compounds including those from the synthetic examples abovewere evaluated and had IC₅₀<10 M in this assay.

Inhibition of other cytokines

By similar methods using peripheral blood monocytic cells, appropriatestimuli, and commercially available ELI SA kits (or other method ofdetection such as radioimmunoassay), for a particular cytokine,inhibition of IL-1, G M-CSF, IL-6 and IL-8 can be demonstrated (forexample, see J. C. Lee et al., 1988, Int. J. Immunopharmacol., 10, 835).

What is claimed is:
 1. A compound of the formula (III):

wherein: E is a heteroatom chosen from —O— and —S—; G is: phenyl,naphthyl, benzocyclobutanyl, dihydronaphthyl, tetrahydronaphthyl,benzocycloheptanyl, benzocycloheptenyl, indanyl, indenyl; pyridinyl,pyridonyl, quinolinyl, dihydroquinolinyl, tetrahydroquinoyl,isoquinolinyl, tetrahydroisoquinoyl, pyridazinyl, pyrimidinyl,pyrazinyl, benzimidazolyl, benzthiazolyl, benzooxazolyl, benzofuranyl,benzothiophenyl, benzpyrazolyl, dihydrobenzofuranyl, dibenzofuranyl,dihydrobenzothiophenyl, benzooxazolonyl, benzo[1,4]oxazin-3-onyl,benzodioxolyl, benzo[1,3]dioxol-2-onyl, benzofuran-3-onyl,tetrahydrobenzopyranyl, indolyl, 2,3-dihydro-1H-indolyl, indolinyl,indolonyl, indolinonyl, phthalimidyl; oxetanyl, tetrahydrothiophenyl,piperidinyl, piperazinyl, morpholino, tetrahydropyranyl, dioxanyl,3,4-dihydro-2H-benzo[1,4]oxazinyl, tertrahydropyridinyl,homopiperidinyl, pyrrolinyl, tetrahydropyrimidinyl, decahydroquinolinyl,decahydroisoquinolinyl, thiomorpholino, dihydropyranyl, oxocanyl orheptacanyl; wherein G is optionally substituted by one or more R₁, R₂ orR₃; Ar is: phenyl, naphthyl, quinolinyl, isoquinolinyl,tetrahydronaphthyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl,benzimidazolyl, benzofuranyl, dihydrobenzofuranyl, indolinyl,benzothienyl, dihydrobenzothienyl, indanyl, indenyl or indolyl eachbeing optionally substituted by one or more R₄ or R₅; X is: a C₅₋₈cycloalkyl or cycloalkenyl optionally substituted with one to two oxogroups or one to three C₁₋₄ alkyl, C₁₋₄ alkoxy or C₁₋₄ alkylamino chainseach being branched or unbranched; aryl, furanyl, thienyl, pyrrolyl,pyrazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyridinonyl,dihydropyridinonyl, maleimidyl, dihydromaleimidyl, piperdinyl,benzimidazole, 3H-imidazo[4,5-b]pyridine, piperazinyl, pyridazinyl orpyrazinyl; each being optionally independently substituted with one tothree C₁₋₄ alkyl, C₁₋₄alkoxy, hydroxy, nitrile, amino, mono- or di-(C₁₋₃alkyl)amino, mono- or di-(C₁₋₃ alkylamino)carbonyl, NH₂C(O), C₁₋₆alkyl-S(O)_(m) or halogen, Y is: a bond or a C₁₋₄ saturated orunsaturated branched or unbranched carbon chain optionally partially orfully halogenated, wherein one or more C atoms are optionally replacedby O, N, or S(O)_(m) and wherein Y is optionally independentlysubstituted with one to two oxo groups, nitrile, phenyl or one or moreC₁₋₄ alkyl optionally substituted by one or more halogen atoms; Z is:aryl, heteroaryl selected from pyridinyl, piperazinyl, pyrimidinyl,pyridazinyl, pyrazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl,furanyl, thienyl and pyranyl, heterocycle selected fromtetrahydropyrimidonyl, cyclohexanonyl, cyclohexanolyl, 2-oxa- or2-thia-5-aza-bicyclo[2.2.1]heptanyl, pentamethylene sulfidyl,pentamethylene sulfoxidyl, pentamethylene sulfonyl, tetramethylenesulfidyl, tetramethylene sulfoxidyl or tetramethylene sulfonyl,tetrahydropyranyl, tetrahydrofuranyl, 1,3-dioxolanonyl, 1,3-dioxanonyl,1,4-dioxanyl, morpholino, thiomorpholino, thiomorpholino sulfoxidyl,thiomorpholino sulfonyl, piperidinyl, piperidinonyl, pyrrolidinyl anddioxolanyl, each of the aforementioned Z are optionally substituted withone to three halogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₃ alkoxy-C₁₋₃ alkyl,C₁₋₆ alkoxycarbonyl, aroyl, C₁₋₃acyl, oxo, hydroxy, pyridinyl-C₁₋₃alkyl, imidazolyl-C₁₋₃ alkyl, tetrahydrofuranyl-C₁₋₃ alkyl, nitrile-C₁₋₃alkyl, nitrile, carboxy, phenyl wherein the phenyl ring is optionallysubstituted with one to two halogen, C₁₋₆ alkoxy, hydroxy or mono- ordi-(C₁₋₃ alkyl)amino, C₁₋₆ alkyl-S(O)_(m), or phenyl-S(O)_(m) whereinthe phenyl ring is optionally substituted with one to two halogen, C₁₋₆alkoxy, hydroxy, halogen or mono- or di-(C₁₋₃ alkyl)amino; or Z isoptionally substitute with one to three amino or amino-C₁₋₃ alkylwherein the N atom is optionally independently mono- or di-substitutedby aminoC₁₋₆alkyl, C₁₋₃alkyl, arylC₀₋₃alkyl, C₁₋₅ alkoxyC₁₋₃ alkyl, C₁₋₅alkoxy, aroyl, C₁₋₃acyl, C₁₋₃alkyl-S(O)_(m)— or arylC₀₋₃alkyl-S(O)_(m)—each of the aforementioned alkyl and aryl attached to the amino group isoptionally substituted with one to two halogen, C₁₋₆ alkyl or C₁₋₆alkoxy; or Z is optionally substitute with one to three aryl,heterocycle or heteroaryl as hereinabove described in this paragrapheach in turn is optionally substituted by halogen, C₁₋₆ alkyl or C₁₋₆alkoxy; each R₁ is independently: C₁₋₁₀ alkyl branched or unbranchedoptionally partially or fully halogenated, wherein one or more C atomsare optionally independently replaced by O, N or S(O)_(m), and whereinsaid C₁₋₁₀ alkyl is optionally substituted with one to three C₃₋₁₀cycloalkyl, hydroxy, oxo, phenyl, naphthyl, pyridinyl, pyrimidinyl,pyrazinyl, pyridazinyl, pyrrolyl, pyrrolidinyl, imidazolyl, pyrazolyl,thienyl, furyl, dioxolanyl, isoxazolyl or isothiazolyl; each of theaforementioned being optionally substituted with one to five groupsselected from halogen, C₁₋₆ alkyl which is optionally partially or fullyhalogenated, C₃₋₈ cycloalkanyl, C₅₋₈ cycloalkenyl, hydroxy, nitrile,C₁₋₃ alkoxy which is optionally partially or fully halogenated orNH₂C(O), mono- or di(C₁₋₃alkyl)amino, and mono- ordi(C₁₋₃alkyl)aminocarbonyl; or R₁ is cyclopropyloxy, cyclobutyloxy,cyclopentyloxy, cyclohexyloxy, or cycloheptyloxy each being optionallypartially or fully halogenated and optionally substituted with one tothree C₁₋₃ alkyl groups optionally partially or fully halogenated,nitrile, hydroxyC₁₋₃alkyl or aryl; or an analog of such cycloalkyl groupwherein one to three ring methylene groups are independently replaced yO, S(O)_(m), CHOH, >C═O, >C═S or NH; phenyloxy or benzyloxy each beingoptionally partially or fully halogenated and optionally substitutedwith one to three C₁₋₃ alkyl groups optionally partially or fullyhalogenated, nitrile, hydroxyC₁₋₃alkyl or aryl; or an analog of suchcycloaryl group wherein one to two ring methyne groups are independentlyreplaced by N; cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, bicyclopentanyl, bicyclohexanyl or bicycloheptanyl, eachbeing optionally partially or fully halogenated and optionallysubstituted with one to three C₁₋₃ alkyl optionally partially or fullyhalogenated, nitrile, hydroxyC₁₋₃alkyl or aryl; or an analog of suchcycloalkyl group wherein one to three ring methylene groups areindependently replaced by O, S(O)_(m), CHOH, >C═O, >C═S or NH; C₃₋₁₀branched or unbranced alkenyl each being optionally partially or fullyhalogenated, and optionally substituted with one to three C₁₋₅ branchedor unbranched alkyl, phenyl, naphthyl, pyridinyl, pyrimidinyl,pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl,isoxazolyl or isothiazolyl, each of the aforementioned being substitutedwith one to five halogen, C₁₋₆ alkyl which is optionally partially orfully halogenated, cyclopropanyl, cyclobutanyl, cyclopentanyl,cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl andbicycloheptanyl, hydroxy, nitrile, C₁₋₃ alkyloxy which is optionallypartially or fully halogenated, NH₂C(O), mono- ordi(C₁₋₃alkyl)aminocarbonyl; the C₃₋₁₀ branched or unbranced alkenylbeing optionally interrupted by one or more heteroatoms chosen from O, Nand S(O)_(m); cyclopentenyl, cyclohexenyl cyclohexadienyl,cycloheptenyl, cycloheptadienyl, bicyclohexenyl or bicycloheptenyl,wherein such cycloalkenyl group is optionally substituted with one tothree C₁₋₃ alkyl groups; oxo, nitrile, halogen; silyl containing threeC₁₋₄ alkyl groups optionally partially or fully halogenated; or C₃₋₆alkynyl branched or unbranched carbon chain optionally partially orfully halogenated, wherein one or more methylene groups are optionallyreplaced by O, NH or S(O)_(m) and wherein said alkynyl group isoptionally independently substituted with one to two oxo groups,hydroxy, pyrroldinyl, pyrrolyl, tetrahydropyranyl, one or more C₁₋₄alkyl optionally substituted by one or more halogen atoms, nitrile,morpholino, piperidinyl, piperazinyl, imidazolyl, phenyl, pyridinyl,tetrazolyl, or mono- or di(C₁₋₃alkyl)amino optionally substituted by oneor more halogen atoms; each R₂, R₄, and R₅ is a C₁₋₆ branched orunbranched alkyl optionally partially or fully halogenated, C₁₋₆acyl,aroyl, C₁₋₄ branched or unbranched alkoxy, each being optionallypartially or fully halogenated, halogen, methoxycarbonyl, C₁₋₃alkyl-S(O)_(m) optionally partially or fully halogenated, orphenyl-S(O)_(m); OR₆, C₁₋₆ alkoxy, hydroxy, nitrile, nitro, halogen; oramino-S(O)_(m)— wherein the N atom is optionally independently mono- ordi-substituted by C₁₋₆alkyl or arylC₀₋₃alkyl or amino wherein the N atomis optionally independently mono- or di-substituted by C₁₋₃alkyl,arylC₀₋₃alkyl, C₁₋₆acyl, C₁₋₆alkyl-S(O)_(m)— or arylC₀₋₃alkyl-S(O)_(m)—,each of the aforementioned alkyl and aryl in this subparagraph areoptionally partially or fully halogenated and optionally substitutedwith one to two C₁₋₆ alkyl or C₁₋₆ alkoxy; each R₃ is independently:phenyl, naphthyl, morpholino, pyridinyl, pyrimidinyl, pyrazinyl,pyridazinyl, pyrrolyl, pyrrolidinyl, imidazolyl, pyrazolyl, thiazolyl,oxazoyl, [1,3,4]oxadiazol, triazolyl, tetrazolyl, thienyl, furyl,tetrahydrofuryl, isoxazolyl, isothiazolyl, quinolinyl, isoquinolinyl,indolyl, benzimidazolyl, benzofuranyl, benzoxazolyl, benzisoxazolyl,benzpyrazolyl, benzothiofuranyl, cinnolinyl, pterindinyl, phthalazinyl,naphthypyridinyl, quinoxalinyl, quinazolinyl, purinyl or indazolyl, eachof the aforementioned is optionally substituted with one to threephenyl, naphthyl, heterocycle or heteroaryl as hereinabove described inthis paragraph, C₁₋₆ branched or unbranched alkyl which is optionallypartially or fully halogenated, cyclopropanyl, cyclobutanyl,cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl,bicyclohexanyl, bicycloheptanyl, phenyl C₁₋₅ alkyl, naphthyl C₁₋₅ alkyl,halogen, hydroxy, oxo, nitrile, C₁₋₃ alkoxy optionally partially orfully halogenated, phenyloxy, naphthyloxy, heteroaryloxy orheterocyclicoxy wherein the heterocyclic or heteroaryl moiety is ashereinabove described in this paragraph, nitro, amino, mono- ordi-(C₁₋₃alky)lamino, phenylamino, naphthylamino, heteroaryl orheterocyclic amino wherein the heteroaryl heterocyclic moiety is ashereinabove described in this paragraph, NH₂C(O), a mono- ordi-(C₁₋₃alkyl) aminocarbonyl, C₁₋₅ alkyl-C(O)—C₁₋₄ alkyl, amino-C₁₋₅alkyl, mono- or di-(C₁₋₅alkyl)amino, mono- or di-(C₁₋₃alkyl)amino-C₁₋₅alkyl, amino-S(O)₂, di-(C₁₋₃alkyl)amino-S(O)₂, R₇—C₁₋₅ alkyl, R₈—C₁₋₅alkoxy, R₉—C(O)—C₁₋₅ alkyl, R₁₀—C₁₋₅ alkyl(R₁₁)N, carboxy-mono- ordi-(C₁₋₅alkyl)-amino; a fused aryl selected from benzocyclobutanyl,indanyl, indenyl, dihydronaphthyl, tetrahydronaphthyl,benzocycloheptanyl and benzocycloheptenyl, or a fused heteroarylselected from cyclopentenopyridinyl, cyclohexanopyridinyl,cyclopentanopyrimidinyl, cyclohexanopyrimidinyl, cyclopentanopyrazinyl,cyclohexanopyrazinyl, cyclopentanopyridazinyl, cyclohexanopyridazinyl,cyclopentanoquinolinyl, cyclohexanoquinolinyl,cyclopentanoisoquinolinyl, cyclohexanoisoquinolinyl,cyclopentanoindolyl, cyclohexanoindolyl, cyclopentanobenzimidazolyl,cyclohexanobenzimidazolyl, cyclopentanobenzoxazolyl,cyclohexanobenzoxazolyl, cyclopentanoimidazolyl, cyclohexanoimidazolyl,cyclopentanothienyl and cyclohexanothienyl; wherein the fused aryl orfused heteroaryl ring is independently substituted with zero to threephenyl, naphthyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl,pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, isoxazolyl,isothiazolyl, C₁₋₆ alkyl which is optionally partially or fullyhalogenated, halogen, nitrile, C₁₋₃ alkyloxy which is optionallypartially or fully halogenated, phenyloxy, naphthyloxy, heteroaryloxy orheterocyclicoxy wherein the heteroaryl or heterocyclic moiety is ashereinabove described in this paragraph, nitro, amino, mono- ordi-(C₁₋₃alkyl)amino, phenylamino, naphthylamino, heteroaryl orheterocyclic amino wherein the heteroaryl or heterocyclic moiety is ashereinabove described in this paragraph, NH₂C(O), mono- ordi-(C₁₋₃alkyl)aminocarbonyl, C₁₋₄ alkyl-OC(O), C₁₋₅ alkyl-C(O)—C₁₋₄alkyl, amino-C₁₋₅ alkyl, mono- or di-(C₁₋₃)alkylamino-C₁₋₅ alkyl,R₁₂—C₁₋₅ alkyl, R₁₃—C₁₋₅ alkoxy, R₁₄—C(O)—C₁₋₅ alkyl or R₁₅—C₁₋₅alkyl(R₁₆)N; cyclopropanyl, cyclobutanyl cyclopentanyl, cyclohexanyl,cycloheptanyl, bicyclopentanyl, bicyclohexanyl or bicycloheptanyl, eachbeing optionally be partially or fully halogenated and optionallysubstituted with one to three C₁₋₃ alkyl groups, or an analog of suchcycloalkyl group wherein one to three ring methylene groups areindependently replaced by O, S, CHOH, >C═O, >C═S or NH; cyclopentenyl,cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl,bicyclohexenyl or bicycloheptenyl, each optionally substituted with oneto three C₁₋₃ alkyl groups; C₁₋₄ alkyl-phenyl-C(O)—C₁₋₄ alkyl-, C₁₋₄alkyl-C(O)—C₁₋₄ alkyl- or C₁₋₄ alkyl-phenyl-S(O)_(m)—C₁₋₄ alkyl-; C₁₋₆alkyl or C₁₋₆ branched unbranched alkoxy each of which is optionallypartially or fully halogenated or optionally substituted with R₁₇; OR₁₈or C₁₋₆ alkyl optionally substituted with OR₁₈; amino or mono- ordi-(C₁₋₅alkyl)amino optionally substituted with R₁₉; R₂₀C(O)N(R₂₁)—,R₂₂O— or R₂₃R₂₄NC(O)—; R₂₆(CH₂)_(m)C(O)N(R₂₁)—, R₂₃R₂₄NC(O)—C₁₋₃alkoxyor R₂₆C(O)(CH₂)_(m)N R₂₁)—; C₂₋₆alkenyl substituted by R₂₃R₂₄NC(O)—;C₂₋₆ alkynyl branched or unbranched carbon chain, optionally partiallyor fully halogenated, wherein one or more methylene groups areoptionally replaced by O, NH, S(O)_(m) and wherein said alkynyl group isoptionally independently substituted with one to two oxo groups,pyrroldinyl, pyrrolyl, morpholino, piperidinyl, piperazinyl, imidazolyl,phenyl, pyridinyl, tetrazolyl one or more C₁₋₄ alkyl optionallysubstituted by one or more halogen atoms, nitrile, morpholino,piperidinyl, piperazinyl, imidazolyl, phenyl, pyridinyl, tetrazolyl, ormono- or di(C₁₋₄ alkyl)amino optionally substituted by one or morehalogen atoms; C₁₋₆acyl or aroyl; R₆ is a: C₁₋₄ alkyl optionallypartially or fully halogenated and optionally substituted with R₂₆; eachR₇, R₈, R₉, R₁₀, R₁₂, R₁₃, R₁₄, R₁₅, R₁₇, R₁₉, R₂₅ and R₂₆ isindependently: nitrile, phenyl, morpholino, piperidinyl, piperazinyl,imidazolyl, pyridinyl, tetrazolyl, amino or mono- or di-(C₁₋₄alkyl)aminooptionally partially or fully halogenated; each R₁₁ and R₁₆ isindependently: hydrogen or C₁₋₄ alkyl optionally partially or frillyhalogenated; R₁₈ is independently: hydrogen or a C₁₋₄ alkyl optionallyindependently substituted with oxo or R₂₅; R₂₀ is independently: C₁₋₁₀alkyl optionally partially or fully halogenated, phenyl, or pyridinyl;R₂₁ is independently: hydrogen or C₁₋₃ alkyl optionally partially orfully halogenated; each R₂₂, R₂₃ and R₂₄ is independently: hydrogen,C₁₋₆ alkyl optionally partially or fully halogenated, said C₁₋₆ alkyl isoptionally interrupted by one or more O, N or S, said C₁₋₆ alkyl alsobeing independently optionally substituted by mono- ordi-(C₁₋₃alkyl)aminocarbonyl, phenyl, pyridinyl, amino or mono- ordi-(C₁₋₄alkyl)amino each of which is optionally partially or fullyhalogenated and optionally substituted with mono- ordi-(C₁₋₃alkyl)amino; or R₂₃ and R₂₄ taken together optionally form aheterocyclic or heteroaryl ring; m=0, 1 or 2; W is O or S andpharmaceutically acceptable derivatives thereof; wherein at least one ofG, Ar, X or Z is a heterocyclic or heteroaryl ring.
 2. The compoundaccording to claim 1 wherein: E is —O—; and W is O.
 3. A compoundwherein the compound is:[4-(6-Morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-carbamic acid3-tert-butyl-phenyl ester and the pharmaceutically acceptablederivatives thereof.
 4. A pharmaceutical composition comprising apharmaceutically effective amount of a compound according to claim
 1. 5.A pharmaceutical composition comprising a pharmaceutically effectiveamount of a compound according to claim
 3. 6. A method of treating adisease mediated by cytokines which comprises administering to a patientin need of such treatment a therapeutically effective amount of acompound according to claim 1 or
 3. 7. The method according to claim 6wherein the cytokine-mediated disease is selected from rheumatoidarthritis, osteoarthritis, Crohn's disease, ulcerative colitis, multiplesclerosis, Guillain-Barre syndrome, psoriasis, graft versus hostdisease, systemic lupus erythematosus, diabetes, toxic shock syndrome,osteoporosis, Alzheimer's disease, acute and chronic pain, contactdermatitis and atherosclerosis.
 8. A method of eating aneutrophil-mediated disease selected from stroke, myocardial infarction,thermal injury, adult respiratory distress syndrome (ARDS), multipleorgan injury secondary to trauma, acute glomerulonephritis, dermatoseswith acute inflammatory components, acute purulent meningitis,hemodialysis, leukopherisis, granulocyte transfusion associatedsyndromes and necrotizing entrerocolitis, which comprises administeringto a patient in need of such treatment a therapeutically effectiveamount of a compound according to claim 1 or 3.